Skip to main content Accessibility help

A Consideration of Biomarkers to be Used for Evaluation of Inflammation in Human Nutritional Studies

  • P.C. Calder (a1), N. Ahluwalia (a2), R. Albers (a3) (a4), N. Bosco (a5), R. Bourdet-Sicard (a6), D. Haller (a7), S.T. Holgate (a1), L.S. Jönsson (a8), M.E. Latulippe (a8), A. Marcos (a9), J. Moreines (a10), C. M'Rini (a11), M. Müller (a12), G. Pawelec (a13), R.J.J. van Neerven (a14), B. Watzl (a15) and J. Zhao (a16)...


To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      A Consideration of Biomarkers to be Used for Evaluation of Inflammation in Human Nutritional Studies
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      A Consideration of Biomarkers to be Used for Evaluation of Inflammation in Human Nutritional Studies
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      A Consideration of Biomarkers to be Used for Evaluation of Inflammation in Human Nutritional Studies
      Available formats


Corresponding author

Correspondence: ILSI Europe a.i.s.b.l., Av. E. Mounier 83, Box 6, 1200 Brussels, Belgium, fax: +32 2 762 00 44, email:


Hide All
1Calder, PC, Albers, R, Antoine, JM, et al. (2009) Inflammatory disease processes and interactions with nutrition. Br J Nutr 101, Suppl. 1, S1S45.
2Sun, S, Ji, Y, Kersten, S, et al. (2012) Mechanisms of inflammatory responses in obese adipose tissue. Annu Rev Nutr 32, 261286.
3Iyer, SS & Cheng, G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32, 2363.
4Fredman, G & Serhan, CN (2011) Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. Biochem J 437, 185197.
5Serhan, CN & Savill, J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6, 11911197.
6Calder, PC, Ahluwalia, N, Brouns, F, et al. (2011) Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 106, S1S78.
7Conde, J, Scotece, M, Gomez, R, et al. (2011) Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Biofactors 37, 413420.
8Kalupahana, NS, Moustaid-Moussa, N & Claycombe, KJ (2012) Immunity as a link between obesity and insulin resistance. Mol Aspects Med 33, 2634.
9Glass, CK & Witztum, JL (2001) Atherosclerosis. The road ahead. Cell 104, 503516.
10Hansson, GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352, 16851695.
11Ross, R (1999) Atherosclerosis – an inflammatory disease. N Engl J Med 340, 115126.
12Biomarkers Definition Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69, 8995.
13Institute of Medicine of the National Academies of Science (2010) Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Washington, DC: The National Academy Press.
14Ferrucci, L, Corsi, A, Lauretani, F, et al. (2005) The origins of age-related proinflammatory state. Blood 105, 22942299.
15Krabbe, KS, Pedersen, M & Bruunsgaard, H (2004) Inflammatory mediators in the elderly. Exp Gerontol 39, 687699.
16Otsuka, R, Tamakoshi, K, Wada, K, et al. (2008) Having more healthy practice was associated with low white blood cell counts in middle-aged Japanese male and female workers. Ind Health 46, 341347.
17Rana, JS, Boekholdt, SM, Ridker, PM, et al. (2007) Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study. J Intern Med 262, 678689.
18Fagiolo, U, Cossarizza, A, Scala, E, et al. (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23, 23752378.
19Pietschmann, P, Gollob, E, Brosch, S, et al. (2003) The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism. Exp Gerontol 38, 11191127.
20Hager, K, Machein, U, Krieger, S, et al. (1994) Interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging 15, 771772.
21Roubenoff, R, Harris, TB, Abad, LW, et al. (1998) Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 53, M20M26.
22Paolisso, G, Rizzo, MR, Mazziotti, G, et al. (1998) Advancing age and insulin resistance: role of plasma tumor necrosis factor-alpha. Am J Physiol 275, E294E299.
23Bruunsgaard, H, Andersen-Ranberg, K, Jeune, B, et al. (1999) A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 54, M357M364.
24Shurin, GV, Yurkovetsky, ZR, Chatta, GS, et al. (2007) Dynamic alteration of soluble serum biomarkers in healthy aging. Cytokine 39, 123129.
25Catania, A, Airaghi, L, Motta, P, et al. (1997) Cytokine antagonists in aged subjects and their relation with cellular immunity. J Gerontol A Biol Sci Med Sci 52, B93B97.
26Yasuma, TR, Nakamura, M, Nishiguchi, KM, et al. (2010) Elevated C-reactive protein levels and ARMS2/HTRA1 gene variants in subjects without age-related macular degeneration. Mol Vis 16, 29232930.
27Akbay, E, Yetkin, I, Ersoy, R, et al. (2004) The relationship between levels of alpha1-acid glycoprotein and metabolic parameters of diabetes mellitus. Diabetes Nutr Metab 17, 331335.
28Aliberti, G, Proietta, M, Pulignano, I, et al. (2010) Association between fibrinogen plasma levels and platelet counts in an outpatient population and in patients with coronary heart disease. Blood Coagul Fibrinolysis 21, 216220.
29Forsey, RJ, Thompson, JM, Ernerudh, J, et al. (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124, 487493.
30Richter, V, Rassoul, F, Purschwitz, K, et al. (2003) Circulating vascular cell adhesion molecules VCAM-1, ICAM-1, and E-selectin in dependence on aging. Gerontology 49, 293300.
31Seidler, S, Zimmermann, HW, Bartneck, M, et al. (2010) Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol 11, 30.
32von Eyben, FE, Mouritsen, E, Holm, J, et al. (2005) Plasminogen activator inhibitor 1 activity and other coronary risk factors. Clin Appl Thromb Hemost 11, 5561.
33Koh, SJ, Hyun, YJ, Choi, SY, et al. (2008) Influence of age and visceral fat area on plasma adiponectin concentrations in women with normal glucose tolerance. Clin Chim Acta 389, 4550.
34Ku, BJ, Kim, SY, Lee, TY, et al. (2009) Serum ferritin is inversely correlated with serum adiponectin level: population-based cross-sectional study. Dis Markers 27, 303310.
35Remarque, E & Pawelec, G (1998) T-cell immunosenescence and its clinical relevance in man. Rev Clin Gerontol 8, 514.
36Strindhall, J, Nilsson, BO, Lofgren, S, et al. (2007) No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 42, 753761.
37Muller, L, Pawelec, G & Derhovanessian, E (2012) The immune system during ageing. In Diet, Immunity and Inflammation [Calder, PC and Yaqoob, P, editors]. Cambridge: Woodhead Publishing.
38Franceschi, C (2007) Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev 65, S173S176.
39Ahluwalia, N (2004) Aging, nutrition and immune function. J Nutr Health Aging 8, 26.
40Lesourd, B (2006) Nutritional factors and immunological ageing. Proc Nutr Soc 65, 319325.
41Larbi, A, Franceschi, C, Mazzatti, D, et al. (2008) Aging of the immune system as a prognostic factor for human longevity. Physiology (Bethesda) 23, 6474.
42Ballou, SP, Lozanski, FB, Hodder, S, et al. (1996) Quantitative and qualitative alterations of acute-phase proteins in healthy elderly persons. Age Ageing 25, 224230.
43Jenny, NS, Tracy, RP, Ogg, MS, et al. (2002) In the elderly, interleukin-6 plasma levels and the − 174G>C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol 22, 20662071.
44Candore, G, Colonna-Romano, G, Balistreri, CR, et al. (2006) Biology of longevity: role of the innate immune system. Rejuvenation Res 9, 143148.
45Bruunsgaard, H (2002) Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. Eur Cytokine Netw 13, 389391.
46Nakhai Pour, HR, Grobbee, DE, Muller, M, et al. (2007) Association of endogenous sex hormone with C-reactive protein levels in middle-aged and elderly men. Clin Endocrinol (Oxf) 66, 394398.
47Guigoz, Y, Dore, J & Schiffrin, EJ (2008) The inflammatory status of old age can be nurtured from the intestinal environment. Curr Opin Clin Nutr Metab Care 11, 1320.
48Biagi, E, Nylund, L, Candela, M, et al. (2010) Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 5, e10667.
49Lio, D, Scola, L, Crivello, A, et al. (2003) Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10 − 1082 promoter SNP and its interaction with TNF-alpha − 308 promoter SNP. J Med Genet 40, 296299.
50Iannitti, T & Palmieri, B (2011) Inflammation and genetics: an insight in the centenarian model. Hum Biol 83, 531559.
51Weisberg, SP, McCann, D, Desai, M, et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 17961808.
52Lee, YJ, Shin, YH, Kim, JK, et al. (2010) Metabolic syndrome and its association with white blood cell count in children and adolescents in Korea: the 2005 Korean National Health and Nutrition Examination Survey. Nutr Metab Cardiovasc Dis 20, 165172.
53Margolis, KL, Manson, JE, Greenland, P, et al. (2005) Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women's Health Initiative Observational Study. Arch Intern Med 165, 500508.
54Skinner, AC, Steiner, MJ, Henderson, FW, et al. (2010) Multiple markers of inflammation and weight status: cross-sectional analyses throughout childhood. Pediatrics 125, e801e809.
55Corica, F, Allegra, A, Corsonello, A, et al. (1999) Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects. Int J Obes Relat Metab Disord 23, 355360.
56Winkler, G, Lakatos, P, Salamon, F, et al. (1999) Elevated serum TNF-alpha level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients. Diabet Med 16, 207211.
57Ziccardi, P, Nappo, F, Giugliano, G, et al. (2002) Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105, 804809.
58Meier, CA, Bobbioni, E, Gabay, C, et al. (2002) IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J Clin Endocrinol Metab 87, 11841188.
59Hofso, D, Ueland, T, Hager, H, et al. (2009) Inflammatory mediators in morbidly obese subjects: associations with glucose abnormalities and changes after oral glucose. Eur J Endocrinol 161, 451458.
60Ueland, T, Kristo, C, Godang, K, et al. (2003) Interleukin-1 receptor antagonist is associated with fat distribution in endogenous Cushing's syndrome: a longitudinal study. J Clin Endocrinol Metab 88, 14921496.
61Bastard, JP, Jardel, C, Bruckert, E, et al. (2000) Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 85, 33383342.
62Yudkin, JS, Stehouwer, CD, Emeis, JJ, et al. (1999) C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19, 972978.
63Kim, CS, Park, HS, Kawada, T, et al. (2006) Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) 30, 13471355.
64Straczkowski, M, Dzienis-Straczkowska, S, Stepien, A, et al. (2002) Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin Endocrinol Metab 87, 46024606.
65Christiansen, T, Richelsen, B & Bruun, JM (2005) Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes (Lond) 29, 146150.
66Schernthaner, GH, Kopp, HP, Kriwanek, S, et al. (2006) Effect of massive weight loss induced by bariatric surgery on serum levels of interleukin-18 and monocyte-chemoattractant-protein-1 in morbid obesity. Obes Surg 16, 709715.
67Tchernof, A, Nolan, A, Sites, CK, et al. (2002) Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation 105, 564569.
68Visser, M, Bouter, LM, McQuillan, GM, et al. (1999) Elevated C-reactive protein levels in overweight and obese adults. JAMA 282, 21312135.
69Zhao, Y, He, X, Shi, X, et al. (2010) Association between serum amyloid A and obesity: a meta-analysis and systematic review. Inflamm Res 59, 323334.
70Hanusch-Enserer, U, Zorn, G, Wojta, J, et al. (2009) Non-conventional markers of atherosclerosis before and after gastric banding surgery. Eur Heart J 30, 15161524.
71Roberts, CK, Won, D, Pruthi, S, et al. (2006) Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors. J Appl Physiol 100, 16571665.
72Russell, M, Mendes, N, Miller, KK, et al. (2010) Visceral fat is a negative predictor of bone density measures in obese adolescent girls. J Clin Endocrinol Metab 95, 12471255.
73Thompson, AM, Zhang, Y, Tong, W, et al. (2011) Association of obesity and biomarkers of inflammation and endothelial dysfunction in adults in Inner Mongolia, China. Int J Cardiol 150, 247252.
74Zanni, MV, Stanley, TL, Makimura, H, et al. (2010) Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation. Clin Endocrinol (Oxf) 73, 4854.
75Maachi, M, Pieroni, L, Bruckert, E, et al. (2004) Systemic low-grade inflammation is related to both circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women. Int J Obes Relat Metab Disord 28, 993997.
76Arita, Y, Kihara, S, Ouchi, N, et al. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257, 7983.
77Inadera, H (2008) The usefulness of circulating adipokine levels for the assessment of obesity-related health problems. Int J Med Sci 5, 248262.
78Yang, WS, Lee, WJ, Funahashi, T, et al. (2001) Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86, 38153819.
79Weiss, R (2007) Fat distribution and storage: how much, where, and how? Eur J Endocrinol 157, Suppl. 1, S39S45.
80Greenfield, JR & Campbell, LV (2006) Relationship between inflammation, insulin resistance and type 2 diabetes: ‘cause or effect’? Curr Diabetes Rev 2, 195211.
81Rabkin, SW (2007) Epicardial fat: properties, function and relationship to obesity. Obes Rev 8, 253261.
82Silaghi, A, Piercecchi-Marti, MD, Grino, M, et al. (2008) Epicardial adipose tissue extent: relationship with age, body fat distribution, and coronaropathy. Obesity (Silver Spring) 16, 24242430.
83Ondrak, KS & Hackney, AC (2010) Body composition differences in normal weight, obese-overweight and anorexic adolescents: role of adipocytokines. Med Sport Sci 55, 3242.
84Nakajima, K, Yamaoka, H, Morita, K, et al. (2009) Elderly people with low body weight may have subtle low-grade inflammation. Obesity (Silver Spring) 17, 803808.
85Stephens, NA, Skipworth, RJ & Fearon, KC (2008) Cachexia, survival and the acute phase response. Curr Opin Support Palliat Care 2, 267274.
86Martinez-Gomez, D, Eisenmann, JC, Gomez-Martinez, S, et al. (2011) Sleep duration and emerging cardiometabolic risk markers in adolescents. The AFINOS study. Sleep Med 12, 9971002.
87Walsh, NP, Gleeson, M, Shephard, RJ, et al. (2011) Position statement. Part one: immune function and exercise. Exerc Immunol Rev 17, 663.
88Walsh, NP, Gleeson, M, Pyne, DB, et al. (2011) Position statement. Part two: maintaining immune health. Exerc Immunol Rev 17, 64103.
89Johannsen, NM, Priest, EL, Dixit, VD, et al. (2010) Association of white blood cell subfraction concentration with fitness and fatness. Br J Sports Med 44, 588593.
90Hamer, M (2007) The relative influences of fitness and fatness on inflammatory factors. Prev Med 44, 311.
91Abramson, JL & Vaccarino, V (2002) Relationship between physical activity and inflammation among apparently healthy middle-aged and older US adults. Arch Intern Med 162, 12861292.
92King, DE, Carek, P, Mainous, AG, et al. (2003) Inflammatory markers and exercise: differences related to exercise type. Med Sci Sports Exerc 35, 575581.
93Mora, S, Lee, IM, Buring, JE, et al. (2006) Association of physical activity and body mass index with novel and traditional cardiovascular biomarkers in women. JAMA 295, 14121419.
94Panagiotakos, DB, Pitsavos, C, Chrysohoou, C, et al. (2005) The associations between leisure-time physical activity and inflammatory and coagulation markers related to cardiovascular disease: the ATTICA Study. Prev Med 40, 432437.
95Pischon, T, Hankinson, SE, Hotamisligil, GS, et al. (2003) Leisure-time physical activity and reduced plasma levels of obesity-related inflammatory markers. Obes Res 11, 10551064.
96Wannamethee, SG, Lowe, GD, Whincup, PH, et al. (2002) Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 105, 17851790.
97Raitakari, M, Mansikkaniemi, K, Marniemi, J, et al. (2005) Distribution and determinants of serum high-sensitive C-reactive protein in a population of young adults: The Cardiovascular Risk in Young Finns Study. J Intern Med 258, 428434.
98Church, TS, Barlow, CE, Earnest, CP, et al. (2002) Associations between cardiorespiratory fitness and C-reactive protein in men. Arterioscler Thromb Vasc Biol 22, 18691876.
99Bautmans, I, Njemini, R, Vasseur, S, et al. (2005) Biochemical changes in response to intensive resistance exercise training in the elderly. Gerontology 51, 253265.
100Fischer, CP, Plomgaard, P, Hansen, AK, et al. (2004) Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle. Am J Physiol Endocrinol Metab 287, E1189E1194.
101Hammett, CJ, Oxenham, HC, Baldi, JC, et al. (2004) Effect of six months’ exercise training on C-reactive protein levels in healthy elderly subjects. J Am Coll Cardiol 44, 24112413.
102Hammett, CJ, Prapavessis, H, Baldi, JC, et al. (2006) Effects of exercise training on 5 inflammatory markers associated with cardiovascular risk. Am Heart J 151, 367e7367e16.
103Lakka, TA, Lakka, HM, Rankinen, T, et al. (2005) Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study. Eur Heart J 26, 20182025.
104Marcell, TJ, McAuley, KA, Traustadottir, T, et al. (2005) Exercise training is not associated with improved levels of C-reactive protein or adiponectin. Metabolism 54, 533541.
105Nicklas, BJ, Ambrosius, W, Messier, SP, et al. (2004) Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial. Am J Clin Nutr 79, 544551.
106Martinez-Gomez, D, Gomez-Martinez, S, Ruiz, JR, et al. (2012) Objectively-measured and self-reported physical activity and fitness in relation to inflammatory markers in European adolescents: the HELENA Study. Atherosclerosis 221, 260267.
107Milani, RV, Lavie, CJ & Mehra, MR (2004) Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol 43, 10561061.
108Rankovic, G, Milicic, B, Savic, T, et al. (2009) Effects of physical exercise on inflammatory parameters and risk for repeated acute coronary syndrome in patients with ischemic heart disease. Vojnosanit Pregl 66, 4448.
109Martinez-Gomez, D, Eisenmann, JC, Gomez-Martinez, S, et al. (2012) Associations of physical activity and fitness with adipocytokines in adolescents: the AFINOS Study. Nutr Metab Cardiovasc Dis 22, 252259.
110Marques-Vidal, P, Bochud, M, Bastardot, F, et al. (2011) Levels and determinants of inflammatory biomarkers in a Swiss population-based sample (CoLaus study). PLoS One 6, e21002.
111Bouman, A, Schipper, M, Heineman, MJ, et al. (2004) Gender difference in the non-specific and specific immune response in humans. Am J Reprod Immunol 52, 1926.
112Durham, A, Chou, PC, Kirkham, P, et al. (2010) Epigenetics in asthma and other inflammatory lung diseases. Epigenomics 2, 523537.
113Trenkmann, M, Brock, M, Ospelt, C, et al. (2010) Epigenetics in rheumatoid arthritis. Clin Rev Allergy Immunol 39, 1019.
114Wierda, RJ, Geutskens, SB, Jukema, JW, et al. (2010) Epigenetics in atherosclerosis and inflammation. J Cell Mol Med 14, 12251240.
115Wilson, AG (2008) Epigenetic regulation of gene expression in the inflammatory response and relevance to common diseases. J Periodontol 79, 15141519.
116Fishman, D, Faulds, G, Jeffery, R, et al. (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102, 13691376.
117Jacob, CO, Fronek, Z, Lewis, GD, et al. (1990) Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci U S A 87, 12331237.
118Messer, G, Spengler, U, Jung, MC, et al. (1991) Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. J Exp Med 173, 209219.
119Santtila, S, Savinainen, K & Hurme, M (1998) Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 47, 195198.
120Stuber, F, Petersen, M, Bokelmann, F, et al. (1996) A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 24, 381384.
121Kelberman, D, Fife, M, Rockman, MV, et al. (2004) Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery. Biochim Biophys Acta 1688, 160167.
122Wilson, AG, Gordon, C, di Giovine, FS, et al. (1994) A genetic association between systemic lupus erythematosus and tumor necrosis factor alpha. Eur J Immunol 24, 191195.
123Wilson, AG, di Giovine, FS & Duff, GW (1995) Genetics of tumour necrosis factor-alpha in autoimmune, infectious, and neoplastic diseases. J Inflamm 45, 112.
124Read, RC, Camp, NJ, di Giovine, FS, et al. (2000) An interleukin-1 genotype is associated with fatal outcome of meningococcal disease. J Infect Dis 182, 15571560.
125Howell, WM, Turner, SJ, Collins, A, et al. (2002) Influence of TNFalpha and LTalpha single nucleotide polymorphisms on susceptibility to and prognosis in cutaneous malignant melanoma in the British population. Eur J Immunogenet 29, 1723.
126Miller, MA & Cappuccio, FP (2007) Ethnicity and inflammatory pathways – implications for vascular disease, vascular risk and therapeutic intervention. Curr Med Chem 14, 14091425.
127Shah, T, Newcombe, P, Smeeth, L, et al. (2010) Ancestry as a determinant of mean population C-reactive protein values: implications for cardiovascular risk prediction. Circ Cardiovasc Genet 3, 436444.
128Ernst, E (1995) Haemorheological consequences of chronic cigarette smoking. J Cardiovasc Risk 2, 435439.
129Holz, T, Thorand, B, Doring, A, et al. (2010) Markers of inflammation and weight change in middle-aged adults: results from the prospective MONICA/KORA S3/F3 study. Obesity (Silver Spring) 18, 23472353.
130Bermudez, EA, Rifai, N, Buring, JE, et al. (2002) Relation between markers of systemic vascular inflammation and smoking in women. Am J Cardiol 89, 11171119.
131Helmersson, J, Larsson, A, Vessby, B, et al. (2005) Active smoking and a history of smoking are associated with enhanced prostaglandin F(2alpha), interleukin-6 and F2-isoprostane formation in elderly men. Atherosclerosis 181, 201207.
132Woodward, M, Rumley, A, Tunstall-Pedoe, H, et al. (1999) Associations of blood rheology and interleukin-6 with cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 104, 246257.
133Petrescu, F, Voican, SC & Silosi, I (2010) Tumor necrosis factor-alpha serum levels in healthy smokers and nonsmokers. Int J Chron Obstruct Pulmon Dis 5, 217222.
134Wirtz, PH, von, KR, Kunz-Ebrecht, S, et al. (2004) Enhanced glucocorticoid sensitivity of cytokine release from circulating leukocytes stimulated with lipopolysaccharide in healthy male smokers. Brain Behav Immun 18, 536543.
135Bazzano, LA, He, J, Muntner, P, et al. (2003) Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 138, 891897.
136Frohlich, M, Sund, M, Lowel, H, et al. (2003) Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J 24, 13651372.
137Lind, P, Engstrom, G, Stavenow, L, et al. (2004) Risk of myocardial infarction and stroke in smokers is related to plasma levels of inflammation-sensitive proteins. Arterioscler Thromb Vasc Biol 24, 577582.
138Lowe, GD, Yarnell, JW, Rumley, A, et al. (2001) C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? Arterioscler Thromb Vasc Biol 21, 603610.
139Wannamethee, SG, Lowe, GD, Shaper, AG, et al. (2005) Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J 26, 17651773.
140Yarnell, JW, Sweetnam, PM, Rumley, A, et al. (2000) Lifestyle and hemostatic risk factors for ischemic heart disease: the Caerphilly Study. Arterioscler Thromb Vasc Biol 20, 271279.
141Bergmann, S, Siekmeier, R, Mix, C, et al. (1998) Even moderate cigarette smoking influences the pattern of circulating monocytes and the concentration of sICAM-1. Respir Physiol 114, 269275.
142Chiu, YH, Spiegelman, D, Dockery, DW, et al. (2011) Secondhand smoke exposure and inflammatory markers in nonsmokers in the trucking industry. Environ Health Perspect 119, 12941300.
143Venn, A & Britton, J (2007) Exposure to secondhand smoke and biomarkers of cardiovascular disease risk in never-smoking adults. Circulation 115, 990995.
144Jefferis, BJ, Lowe, GD, Welsh, P, et al. (2010) Secondhand smoke (SHS) exposure is associated with circulating markers of inflammation and endothelial function in adult men and women. Atherosclerosis 208, 550556.
145Chow, J, Tang, H & Mazmanian, SK (2011) Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol 23, 473480.
146Lomax, AR & Calder, PC (2009) Probiotics, immune function, infection and inflammation: a review of the evidence from studies conducted in humans. Curr Pharm Des 15, 14281518.
147Chervonsky, AV (2012) Intestinal commensals: influence on immune system and tolerance to pathogens. Curr Opin Immunol 24, 255260.
148Wu, HJ & Wu, E (2012) The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3, 414.
149Maslowski, KM & Mackay, CR (2011) Diet, gut microbiota and immune responses. Nat Immunol 12, 59.
150Jiang, HQ, Kushnir, N, Thurnheer, MC, et al. (2002) Monoassociation of SCID mice with Helicobacter muridarum, but not four other enterics, provokes IBD upon receipt of T cells. Gastroenterology 122, 13461354.
151Seksik, P (2010) [Gut microbiota and IBD]. Gastroenterol Clin Biol 34, Suppl. 1, S44S51.
152Peterson, DA, Frank, DN, Pace, NR, et al. (2008) Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 3, 417427.
153Walker, AW, Ince, J, Duncan, SH, et al. (2011) Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J 5, 220230.
154Walker, AW, Sanderson, JD, Churcher, C, et al. (2011) High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 11, 7.
155Sokol, H, Pigneur, B, Watterlot, L, et al. (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105, 1673116736.
156Sokol, H, Seksik, P, Furet, JP, et al. (2009) Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 15, 11831189.
157Claes, IJ, De Keersmaecker, SC, Vanderleyden, J, et al. (2011) Lessons from probiotic–host interaction studies in murine models of experimental colitis. Mol Nutr Food Res 55, 14411453.
158Gareau, MG, Sherman, PM & Walker, WA (2010) Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol 7, 503514.
159Cogen, AL, Nizet, V & Gallo, RL (2008) Skin microbiota: a source of disease or defence? Br J Dermatol 158, 442455.
160Hilty, M, Burke, C, Pedro, H, et al. (2010) Disordered microbial communities in asthmatic airways. PLoS One 5, e8578.
161Huang, YJ, Kim, E, Cox, MJ, et al. (2010) A persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations. OMICS 14, 959.
162Huang, YJ, Nelson, CE, Brodie, EL, et al. (2011) Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 127, 372381.
163Paulino, LC, Tseng, CH, Strober, BE, et al. (2006) Molecular analysis of fungal microbiota in samples from healthy human skin and psoriatic lesions. J Clin Microbiol 44, 29332941.
164Paulino, LC, Tseng, CH & Blaser, MJ (2008) Analysis of Malassezia microbiota in healthy superficial human skin and in psoriatic lesions by multiplex real-time PCR. FEMS Yeast Res 8, 460471.
165Delzenne, NM & Cani, PD (2011) Interaction between obesity and the gut microbiota: relevance in nutrition. Annu Rev Nutr 31, 1531.
166Penders, J, Stobberingh, EE, van den Brandt, PA, et al. (2007) The role of the intestinal microbiota in the development of atopic disorders. Allergy 62, 12231236.
167Cani, PD, Osto, M, Geurts, L, et al. (2012) Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 3, 279288.
168Clarke, S, Murphy, E, Nilaweera, K, et al. (2012) The gut microbiota and its relationship to diet and obesity: new insights. Gut Microbes 3, 186202.
169Serino, M, Luche, E, Gres, S, et al. (2011) Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 61, 543553.
170Cani, PD, Bibiloni, R, Knauf, C, et al. (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 14701481.
171Furet, JP, Kong, LC, Tap, J, et al. (2010) Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 30493057.
172Turnbaugh, PJ, Ley, RE, Mahowald, MA, et al. (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 10271031.
173Ley, RE, Turnbaugh, PJ, Klein, S, et al. (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444, 10221023.
174Jumpertz, R, Le, DS, Turnbaugh, PJ, et al. (2011) Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr 94, 5865.
175Gouin, JP, Hantsoo, L & Kiecolt-Glaser, JK (2008) Immune dysregulation and chronic stress among older adults: a review. Neuroimmunomodulation 15, 251259.
176Marshall, GD Jr (2011) The adverse effects of psychological stress on immunoregulatory balance: applications to human inflammatory diseases. Immunol Allergy Clin North Am 31, 133140.
177Heffner, KL (2011) Neuroendocrine effects of stress on immunity in the elderly: implications for inflammatory disease. Immunol Allergy Clin North Am 31, 95108.
178van Eeden, SF, Yeung, A, Quinlam, K, et al. (2005) Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2, 6167.
179Lorton, D, Lubahn, CL, Estus, C, et al. (2006) Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 13, 357374.
180Huber, M, Knottnerus, JA, Green, L, et al. (2011) How should we define health? BMJ 343, d4163.
181van Ommen, B, Keijer, J, Heil, SG, et al. (2009) Challenging homeostasis to define biomarkers for nutrition related health. Mol Nutr Food Res 53, 795804.
182Antuna-Puente, B, Disse, E, Rabasa-Lhoret, R, et al. (2011) How can we measure insulin sensitivity/resistance? Diabetes Metab 37, 179188.
183van Leeuwen, M, Louwerse, M, Opmeer, B, et al. (2012) Glucose challenge test for detecting gestational diabetes mellitus: a systematic review. BJOG 119, 393401.
184World Health Organization (2006) Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: Report of a WHO/IDF Consultation. Geneva: WHO.
185O'Keefe, JH & Bell, DS (2007) Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol 100, 899904.
186Derosa, G, D'Angelo, A, Salvadeo, SA, et al. (2010) Oral glucose tolerance test effects on endothelial inflammation markers in healthy subjects and diabetic patients. Horm Metab Res 42, 813.
187Burdge, GC & Calder, PC (2005) Plasma cytokine response during the postprandial period: a potential causal process in vascular disease? Br J Nutr 93, 39.
188Ceriello, A, Assaloni, R, Da Ros, R, et al. (2005) Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 111, 25182524.
189Esposito, K, Nappo, F, Marfella, R, et al. (2002) Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106, 20672072.
190Kempf, K, Rose, B, Herder, C, et al. (2006) Inflammation in metabolic syndrome and type 2 diabetes: impact of dietary glucose. Ann N Y Acad Sci 1084, 3048.
191Frood, A (2010) Technology: a flavour of the future. Nature 468, S21S22.
192Esposito, K, Pontillo, A, Di Palo, C, et al. (2003) Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289, 17991804.
193Derosa, G, Ferrari, I, D'Angelo, A, et al. (2009) Oral fat load effects on inflammation and endothelial stress markers in healthy subjects. Heart Vessels 24, 204210.
194Taudorf, S, Krabbe, KS, Berg, RM, et al. (2007) Human models of low-grade inflammation: bolus versus continuous infusion of endotoxin. Clin Vaccine Immunol 14, 250255.
195Starkie, R, Ostrowski, SR, Jauffred, S, et al. (2003) Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 17, 884886.
196Hojman, P, Taudorf, S, Lundby, C, et al. (2009) Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans. Cytokine 45, 154157.
197Erikstrup, C, Ullum, H & Pedersen, BK (2006) Short-term simvastatin treatment has no effect on plasma cytokine response in a human in vivo model of low-grade inflammation. Clin Exp Immunol 144, 94100.
198Krogh-Madsen, R, Moller, K, Dela, F, et al. (2004) Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans. Am J Physiol Endocrinol Metab 286, E766E772.
199Harrison, NA, Brydon, L, Walker, C, et al. (2009) Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry 66, 415422.
200Carty, CL, Heagerty, P, Nakayama, K, et al. (2006) Inflammatory response after influenza vaccination in men with and without carotid artery disease. Arterioscler Thromb Vasc Biol 26, 27382744.
201Lanza, GA, Barone, L, Scalone, G, et al. (2011) Inflammation-related effects of adjuvant influenza A vaccination on platelet activation and cardiac autonomic function. J Intern Med 269, 118125.
202Trzonkowski, P, Mysliwska, J, Pawelec, G, et al. (2009) From bench to bedside and back: the SENIEUR Protocol and the efficacy of influenza vaccination in the elderly. Biogerontology 10, 8394.
203Glaser, R, Robles, TF, Sheridan, J, et al. (2003) Mild depressive symptoms are associated with amplified and prolonged inflammatory responses after influenza virus vaccination in older adults. Arch Gen Psychiatry 60, 10091014.
204Wright, CE, Strike, PC, Brydon, L, et al. (2005) Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun 19, 345350.
205Werba, JP, Veglia, F, Amato, M, et al. (2008) Patients with a history of stable or unstable coronary heart disease have different acute phase responses to an inflammatory stimulus. Atherosclerosis 196, 835840.
206Dehqanzada, ZA, Storrer, CE, Hueman, MT, et al. (2007) Assessing serum cytokine profiles in breast cancer patients receiving a HER2/neu vaccine using Luminex technology. Oncol Rep 17, 687694.
207Mysliwska, J, Trzonkowski, P, Szmit, E, et al. (2004) Immunomodulating effect of influenza vaccination in the elderly differing in health status. Exp Gerontol 39, 14471458.
208Trzonkowski, P, Mysliwska, J, Szmit, E, et al. (2003) Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination-an impact of immunosenescence. Vaccine 21, 38263836.
209Meydani, SN, Barklund, MP, Liu, S, et al. (1990) Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 52, 557563.
210Pallast, EG, Schouten, EG, de Waart, FG, et al. (1999) Effect of 50- and 100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons. Am J Clin Nutr 69, 12731281.
211Wolvers, DA, van Herpen-Broekmans, WM, Logman, MH, et al. (2006) Effect of a mixture of micronutrients, but not of bovine colostrum concentrate, on immune function parameters in healthy volunteers: a randomized placebo-controlled study. Nutr J 5, 28.
212Pence, BD, Lowder, TW, Keylock, KT, et al. (2012) Relationship between systemic inflammation and delayed-type hypersensitivity response to Candida antigen in older adults. PLoS One 7, e36403.
213Zachariae, R, Jorgensen, MM, Christensen, S, et al. (1997) Effects of relaxation on the delayed-type hypersensitivity (DTH) reaction to diphenylcyclopropenone (DCP). Allergy 52, 760764.
214Sleijffers, A, Garssen, J, de Gruijl, FR, et al. (2001) Influence of ultraviolet B exposure on immune responses following hepatitis B vaccination in human volunteers. J Invest Dermatol 117, 11441150.
215Harper Smith, AD, Coakley, SL, Ward, MD, et al. (2011) Exercise-induced stress inhibits both the induction and elicitation phases of in vivo T-cell-mediated immune responses in humans. Brain Behav Immun 25, 11361142.
216Pedersen, BK & Hoffman-Goetz, L (2000) Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev 80, 10551081.
217Castellano, V, Patel, DI & White, LJ (2008) Cytokine responses to acute and chronic exercise in multiple sclerosis. J Appl Physiol 104, 16971702.
218Kinugawa, T, Kato, M, Ogino, K, et al. (2003) Interleukin-6 and tumor necrosis factor-alpha levels increase in response to maximal exercise in patients with chronic heart failure. Int J Cardiol 87, 8390.
219Kop, WJ, Weissman, NJ, Zhu, J, et al. (2008) Effects of acute mental stress and exercise on inflammatory markers in patients with coronary artery disease and healthy controls. Am J Cardiol 101, 767773.
220Lucia, A, Smith, L, Naidoo, M, et al. (2008) McArdle disease: another systemic low-inflammation disorder? Neurosci Lett 431, 106111.
221van Helvoort, HA, van de Pol, MH, Heijdra, YF, et al. (2005) Systemic inflammatory response to exhaustive exercise in patients with chronic obstructive pulmonary disease. Respir Med 99, 15551567.
222Mercken, EM, Gosker, HR, Rutten, EP, et al. (2009) Systemic and pulmonary oxidative stress after single-leg exercise in COPD. Chest 136, 12911300.
223Rabinovich, RA, Figueras, M, Ardite, E, et al. (2003) Increased tumour necrosis factor-alpha plasma levels during moderate-intensity exercise in COPD patients. Eur Respir J 21, 789794.
224Ionescu, AA, Mickleborough, TD, Bolton, CE, et al. (2006) The systemic inflammatory response to exercise in adults with cystic fibrosis. J Cyst Fibros 5, 105112.
225van Helvoort, HA, Heijdra, YF, de Boer, RC, et al. (2007) Six-minute walking-induced systemic inflammation and oxidative stress in muscle-wasted COPD patients. Chest 131, 439445.
226Ploeger, HE, Takken, T, de Greef, MH, et al. (2009) The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exerc Immunol Rev 15, 641.
227Gilmour, JW, Vestey, JP, George, S, et al. (1993) Effect of phototherapy and urocanic acid isomers on natural killer cell function. J Invest Dermatol 101, 169174.
228Jones, CD, Guckian, M, el-Ghorr, AA, et al. (1996) Effects of phototherapy on the production of cytokines by peripheral blood mononuclear cells and on systemic antibody responses in patients with psoriasis. Photodermatol Photoimmunol Photomed 12, 204210.
229McLoone, P, Man, I, Yule, S, et al. (2004) Whole-body UVB (TL-01) or UVA-1 irradiation does not alter the levels of immunomodulatory cytokines in the serum of human volunteers. Photodermatol Photoimmunol Photomed 20, 7680.
230Narbutt, J, Lesiak, A, Skibinska, M, et al. (2005) Repeated doses of UVR cause minor alteration in cytokine serum levels in humans. Mediators Inflamm 2005, 298303.
231Angst, MS, Clark, JD, Carvalho, B, et al. (2008) Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: a microdialysis study. Pain 139, 1527.
232Averbeck, M, Beilharz, S, Bauer, M, et al. (2006) In situ profiling and quantification of cytokines released during ultraviolet B-induced inflammation by combining dermal microdialysis and protein microarrays. Exp Dermatol 15, 447454.
233Brink, N, Szamel, M, Young, AR, et al. (2000) Comparative quantification of IL-1beta, IL-10, IL-10r, TNFalpha and IL-7 mRNA levels in UV-irradiated human skin in vivo. Inflamm Res 49, 290296.
234Rhodes, LE, Gledhill, K, Masoodi, M, et al. (2009) The sunburn response in human skin is characterized by sequential eicosanoid profiles that may mediate its early and late phases. FASEB J 23, 39473956.
235Wopereis, S, Rubingh, CM, van Erk, MJ, et al. (2009) Metabolic profiling of the response to an oral glucose tolerance test detects subtle metabolic changes. PLoS One 4, e4525.
236Seiler, W, Muller, H & Hiemke, C (1994) Interleukin-6 in plasma collected with an indwelling cannula reflects local, not systemic, concentrations. Clin Chem 40, 17781779.
237Dixon, NC, Hurst, TL, Talbot, DC, et al. (2009) Active middle-aged men have lower fasting inflammatory markers but the postprandial inflammatory response is minimal and unaffected by physical activity status. J Appl Physiol 107, 6368.
238Haack, M, Reichenberg, A, Kraus, T, et al. (2000) Effects of an intravenous catheter on the local production of cytokines and soluble cytokine receptors in healthy men. Cytokine 12, 694698.
239Viardot, A, Lord, RV & Samaras, K (2010) The effects of weight loss and gastric banding on the innate and adaptive immune system in type 2 diabetes and prediabetes. J Clin Endocrinol Metab 95, 28452850.
240Wu, H, Perrard, XD, Wang, Q, et al. (2010) CD11c expression in adipose tissue and blood and its role in diet-induced obesity. Arterioscler Thromb Vasc Biol 30, 186192.
241Derhovanessian, E, Larbi, A & Pawelec, G (2009) Biomarkers of human immunosenescence: impact of Cytomegalovirus infection. Curr Opin Immunol 21, 440445.
242Pawelec, G, Derhovanessian, E, Larbi, A, et al. (2009) Cytomegalovirus and human immunosenescence. Rev Med Virol 19, 4756.
243Pawelec, G, Akbar, A, Caruso, C, et al. (2005) Human immunosenescence: is it infectious? Immunol Rev 205, 257268.
244Wikby, A, Ferguson, F, Forsey, R, et al. (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 60, 556565.
245Wikby, A, Nilsson, BO, Forsey, R, et al. (2006) The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech Ageing Dev 127, 695704.
246Rath, E & Haller, D (2011) Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies. Eur J Nutr 50, 219233.
247Yoshida, H (2009) ER stress response, peroxisome proliferation, mitochondrial unfolded protein response and Golgi stress response. IUBMB Life 61, 871879.
248Renz, H, von Mitius, E, Brandtzaeg, P, et al. (2011) Gene–environment interactions in chronic inflammatory disease. Nat Immunol 12, 273277.
249Bertolotti, A, Wang, X, Novoa, I, et al. (2001) Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest 107, 585593.
250Ji, C, Kaplowitz, N, Lau, MY, et al. (2011) Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54, 229239.
251Kaser, A, Lee, AH, Franke, A, et al. (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743756.
252Haga, N, Saito, S, Tsukumo, Y, et al. (2010) Mitochondria regulate the unfolded protein response leading to cancer cell survival under glucose deprivation conditions. Cancer Sci 101, 11251132.
253Lim, JH, Lee, HJ, Ho, JM, et al. (2009) Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance. Cell Signal 21, 169177.
254Rath, E, Berger, E, Messlik, A, et al. (2012) Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation. Gut 61, 12691278.
255Schroder, M & Kaufman, RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74, 739789.
256Zhao, Q, Wang, J, Levichkin, IV, et al. (2002) A mitochondrial specific stress response in mammalian cells. EMBO J 21, 44114419.
257Sage, AT, Holtby-Ottenhof, S, Shi, Y, et al. (2012) Metabolic syndrome and acute hyperglycemia are associated with endoplasmic reticulum stress in human mononuclear cells. Obesity (Silver Spring) 20, 748755.
258Pockley, AG, Wu, R, Lemne, C, et al. (2000) Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension 36, 303307.
259Pockley, AG, De Faire, U, Kiessling, R, et al. (2002) Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens 20, 18151820.
260Bartel, DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136, 215233.
261Buermans, HP, Ariyurek, Y, van Ommen, G, et al. (2010) New methods for next generation sequencing based microRNA expression profiling. BMC Genomics 11, 716.
262Fichtlscherer, S, Zeiher, AM & Dimmeler, S (2011) Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol 31, 23832390.
263Cortez, MA, Bueso-Ramos, C, Ferdin, J, et al. (2011) MicroRNAs in body fluids-the mix of hormones and biomarkers. Nat Rev Clin Oncol 8, 467477.
264Vickers, KC, Palmisano, BT, Shoucri, BM, et al. (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13, 423433.
265O'Connell, RM, Rao, DS & Baltimore, D (2011) MicroRNA regulation of inflammatory responses. Annu Rev Immunol 30, 295312.
266Zahm, AM, Thayu, M, Hand, NJ, et al. (2011) Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr 53, 2633.
267Cermelli, S, Ruggieri, A, Marrero, JA, et al. (2011) Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One 6, e23937.
268Fichtlscherer, S, De Rosa, S, Fox, H, et al. (2010) Circulating microRNAs in patients with coronary artery disease. Circ Res 107, 677684.
269Bossuyt, X (2006) Serologic markers in inflammatory bowel disease. Clin Chem 52, 171181.
270Dotan, I (2010) New serologic markers for inflammatory bowel disease diagnosis. Dig Dis 28, 418423.
271Reesink, HW, Mohammadi, T, Pietersz, RN, et al. (2008) Rapid screening by real-time 16S rDNA PCR for bacterial contamination of blood products. Clin Chem Lab Med 46, 954962.
272Smith, CJ & Osborn, AM (2009) Advantages and limitations of quantitative PCR (Q-PCR)-based approaches in microbial ecology. FEMS Microbiol Ecol 67, 620.
273Rajendhran, J & Gunasekaran, P (2011) Microbial phylogeny and diversity: small subunit ribosomal RNA sequence analysis and beyond. Microbiol Res 166, 99110.
274Amar, J, Serino, M, Lange, C, et al. (2011) Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54, 30553061.
275 US Environmental Protection Agency (2011) Interim genomics policy.
276Afman, L & Müller, M (2006) Nutrigenomics: from molecular nutrition to prevention of disease. J Am Diet Assoc 106, 569576.
277Müller, M & Kersten, S (2003) Nutrigenomics: goals and strategies. Nat Rev Genet 4, 315322.
278Ordovas, JM & Corella, D (2004) Nutritional genomics. Annu Rev Genomics Hum Genet 5, 71118.
279Wittwer, J, Rubio-Aliaga, I, Hoeft, B, et al. (2011) Nutrigenomics in human intervention studies: current status, lessons learned and future perspectives. Mol Nutr Food Res 55, 341358.
280Afman, LA & Müller, M (2012) Human nutrigenomics of gene regulation by dietary fatty acids. Prog Lipid Res 51, 6370.
281Kussmann, M & Van Bladeren, PJ (2011) The extended nutrigenomics – understanding the interplay between the genomes of food, gut microbes, and human host. Front Genet 2, 21.
282Bouwman, J, Vogels, JT, Wopereis, S, et al. (2012) Visualization and identification of health space, based on personalized molecular phenotype and treatment response to relevant underlying biological processes. BMC Med Genomics 5, 1.
283van Ommen, B, Bouwman, J, Dragsted, LO, et al. (2010) Challenges of molecular nutrition research 6: the nutritional phenotype database to store, share and evaluate nutritional systems biology studies. Genes Nutr 5, 189203.
284de Wit, NJ, Boekschoten, MV, Bachmair, EM, et al. (2011) Dose-dependent effects of dietary fat on development of obesity in relation to intestinal differential gene expression in C57BL/6J mice. PLoS One 6, e19145.
285de Wit, NJ, Bosch-Vermeulen, H, de Groot, PJ, et al. (2008) The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice. BMC Med Genomics 1, 14.
286Duval, C, Thissen, U, Keshtkar, S, et al. (2010) Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice. Diabetes 59, 31813191.
287Grayson, M (2010) Nutrigenomics. Nature 468, S1.
288Laursen, L (2010) Interdisciplinary research: big science at the table. Nature 468, S2S4.
289Bouwens, M, van de Rest, O, Dellschaft, N, et al. (2009) Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr 90, 415424.
290Bakker, GC, van Erk, MJ, Pellis, L, et al. (2010) An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 91, 10441059.
291van Dijk, SJ, Feskens, EJ, Bos, MB, et al. (2009) A saturated fatty acid-rich diet induces an obesity-linked proinflammatory gene expression profile in adipose tissue of subjects at risk of metabolic syndrome. Am J Clin Nutr 90, 16561664.
292van Dijk, SJ, Feskens, EJ, Heidema, AG, et al. (2010) Plasma protein profiling reveals protein clusters related to BMI and insulin levels in middle-aged overweight subjects. PLoS One 5, e14422.
293van Ommen, B, Keijer, J, Kleemann, R, et al. (2008) The challenges for molecular nutrition research 2: quantification of the nutritional phenotype. Genes Nutr 3, 5159.
294Minchin, RF & Martin, DJ (2010) Nanoparticles for molecular imaging – an overview. Endocrinology 151, 474481.
295Pittet, MJ & Weissleder, R (2011) Intravital imaging. Cell 147, 983991.
296Attia, AS, Schroeder, KA, Seeley, EH, et al. (2012) Monitoring the inflammatory response to infection through the integration of MALDI IMS and MRI. Cell Host Microbe 11, 664673.
297Urasaki, Y, Johlfs, MG, Fiscus, RR, et al. (2012) Imaging immune and metabolic cells of visceral adipose tissues with multimodal nonlinear optical microscopy. PLoS One 7, e38418.
298Quillard, T, Croce, K, Jaffer, FA, et al. (2011) Molecular imaging of macrophage protease activity in cardiovascular inflammation in vivo. Thromb Haemost 105, 828836.
299Fuster, V, Lois, F & Franco, M (2010) Early identification of atherosclerotic disease by noninvasive imaging. Nat Rev Cardiol 7, 327333.
300Andreasen, AS, Krabbe, KS, Krogh-Madsen, R, et al. (2008) Human endotoxemia as a model of systemic inflammation. Curr Med Chem 15, 16971705.
301Molteni, M, Della, BS, Mascagni, B, et al. (1994) Secretion of cytokines upon allogeneic stimulation: effect of aging. J Biol Regul Homeost Agents 8, 4147.
302Hise, ME, Compher, C, Harlan, L, et al. (2006) Inflammatory mediators and immune function are altered in home parenteral nutrition patients. Nutrition 22, 97103.
303Gerli, R, Monti, D, Bistoni, O, et al. (2000) Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev 121, 3746.
304Vendrell, J, Broch, M, Fernandez-Real, JM, et al. (2005) Tumour necrosis factor receptors (TNFRs) in Type 2 diabetes. Analysis of soluble plasma fractions and genetic variations of TNFR2 gene in a case–control study. Diabet Med 22, 387392.
305Beharka, AA, Meydani, M, Wu, D, et al. (2001) Interleukin-6 production does not increase with age. J Gerontol A Biol Sci Med Sci 56, B81B88.
306Cohen, HJ, Pieper, CF, Harris, T, et al. (1997) The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol A Biol Sci Med Sci 52, M201M208.
307Wei, J, Xu, H, Davies, JL, et al. (1992) Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci 51, 19531956.
308Rothenbacher, D, Muller-Scholze, S, Herder, C, et al. (2006) Differential expression of chemokines, risk of stable coronary heart disease, and correlation with established cardiovascular risk markers. Arterioscler Thromb Vasc Biol 26, 194199.
309Mariani, E, Cattini, L, Neri, S, et al. (2006) Simultaneous evaluation of circulating chemokine and cytokine profiles in elderly subjects by multiplex technology: relationship with zinc status. Biogerontology 7, 449459.
310Molvarec, A, Szarka, A, Walentin, S, et al. (2011) Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia. Reprod Biol Endocrinol 9, 124.
311Lemieux, I, Pascot, A, Prud'homme, D, et al. (2001) Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 21, 961967.
312Tsai, HJ & Tsai, AC (2008) The association of plasma C-reactive protein levels with anthropometric and lipid parameters in elderly Taiwanese. Asia Pac J Clin Nutr 17, 651656.
313van Dielen, FM, van't Veer, C, Schols, AM, et al. (2001) Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int J Obes Relat Metab Disord 25, 17591766.
314Maple-Brown, LJ, Cunningham, J, Nandi, N, et al. (2010) Fibrinogen and associated risk factors in a high-risk population: urban Indigenous Australians, the DRUID Study. Cardiovasc Diabetol 9, 69.
315Richette, P, Poitou, C, Garnero, P, et al. (2011) Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis. Ann Rheum Dis 70, 139144.
316Cugno, M, Castelli, R, Mari, D, et al. (2012) Inflammatory and prothrombotic parameters in normotensive non-diabetic obese women: effect of weight loss obtained by gastric banding. Intern Emerg Med 7, 237242.
317Giordano, P, Del Vecchio, GC, Cecinati, V, et al. (2011) Metabolic, inflammatory, endothelial and haemostatic markers in a group of Italian obese children and adolescents. Eur J Pediatr 170, 845850.
318Mari, D, Coppola, R & Provenzano, R (2008) Hemostasis factors and aging. Exp Gerontol 43, 6673.
319Valle, JM, Estepa, RM, Camacho, RM, et al. (2007) Endothelial dysfunction is related to insulin resistance and inflammatory biomarker levels in obese prepubertal children. Eur J Endocrinol 156, 497502.
320Hollander, C, Westin, U, Wallmark, A, et al. (2007) Plasma levels of alpha1-antichymotrypsin and secretory leukocyte proteinase inhibitor in healthy and chronic obstructive pulmonary disease (COPD) subjects with and without severe alpha1-antitrypsin deficiency. BMC Pulm Med 7, 1.
321Phillips, CM, Kesse-Guyot, E, Ahluwalia, N, et al. (2012) Dietary fat, abdominal obesity and smoking modulate the relationship between plasma complement component 3 concentrations and metabolic syndrome risk. Atherosclerosis 220, 513519.
322Engström, G, Hedblad, B, Janzon, L, et al. (2005) Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study. Diabetologia 48, 25252531.
323Hermsdorff, HH, Zulet, MA, Abete, I, et al. (2011) A legume-based hypocaloric diet reduces proinflammatory status and improves metabolic features in overweight/obese subjects. Eur J Nutr 50, 6169.
324Onat, A, Hergenc, G, Can, G, et al. (2010) Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism 59, 628634.
325Sakcak, I, Avsar, MF, Hamamci, EO, et al. (2010) Comparison of early and late changes in immunoglobulins and acute phase reactants after laparoscopic adjustable gastric banding in patients with morbid obesity. Obes Surg 20, 610615.
326Salvi, M, Pedrazzoni, M, Girasole, G, et al. (2000) Serum concentrations of proinflammatory cytokines in Graves’ disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking. Eur J Endocrinol 143, 197202.
327Nagayasu, S, Suzuki, S, Yamashita, A, et al. (2012) Smoking and adipose tissue inflammation suppress leptin expression in Japanese obese males: potential mechanism of resistance to weight loss among Japanese obese smokers. Tob Induc Dis 10, 3.
328Albertini, JP, Valensi, P, Lormeau, B, et al. (1998) Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment. Diabetes Care 21, 10081013.
329Zhong, N, Wu, XP, Xu, ZR, et al. (2005) Relationship of serum leptin with age, body weight, body mass index, and bone mineral density in healthy mainland Chinese women. Clin Chim Acta 351, 161168.
330Bergmann, S & Siekmeier, R (2009) Influence of smoking and body weight on adipokines in middle aged women. Eur J Med Res 14, Suppl. 4, 2126.
331Torres, AJ, Angelo, AL, Netto, EM, et al. (2009) Reference range for T lymphocytes populations in blood donors from two different regions in Brazil. Braz J Infect Dis 13, 221225.
332Mathur, SK, Schwantes, EA, Jarjour, NN, et al. (2008) Age-related changes in eosinophil function in human subjects. Chest 133, 412419.
333Tanaka, M, Fukui, M, Tomiyasu, K, et al. (2012) Eosinophil count is positively correlated with coronary artery calcification. Hypertens Res 35, 325328.
334Jensen, EJ, Pedersen, B, Narvestadt, E, et al. (1998) Blood eosinophil and monocyte counts are related to smoking and lung function. Respir Med 92, 6369.
335Della, BS, Bierti, L, Presicce, P, et al. (2007) Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol 122, 220228.
336MacLennon, ICM, Drayson, MT & Tuddenham, EGC (1999) Normal lymphocytes and non-neoplastic lymphocyte disorders. In Postgraduate Haematology [Hoffbrand, AV and Lewis, SM, editors]. Oxford: Butterworth Heinemann.
337Heesen, C, Gold, SM, Hartmann, S, et al. (2003) Endocrine and cytokine responses to standardized physical stress in multiple sclerosis. Brain Behav Immun 17, 473481.
338Mehta, NN, McGillicuddy, FC, Anderson, PD, et al. (2010) Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes 59, 172181.
339Michaeli, B, Berger, MM, Revelly, JP, et al. (2007) Effects of fish oil on the neuro-endocrine responses to an endotoxin challenge in healthy volunteers. Clin Nutr 26, 7077.
340Brydon, L, Walker, C, Wawrzyniak, A, et al. (2009) Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans. Brain Behav Immun 23, 217224.