Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-qxdb6 Total loading time: 0 Render date: 2024-04-25T09:50:41.606Z Has data issue: false hasContentIssue false

3 - Cytokines and sickness behavior: a model for cancer symptoms

from Section 1 - Introduction

Published online by Cambridge University Press:  05 August 2011

By
Steven S. Zalcman ,
Randall T. Woodruff ,
Ruchika Mohla  and
Allan Siegel
Edited by
Charles S. Cleeland ,
Michael J. Fisch  and
Adrian J. Dunn
Steven S. Zalcman
Affiliation:
University of Medicine & Dentistry of New Jersey – New Jersey Medical School
Randall T. Woodruff
Affiliation:
University of Medicine & Dentistry of New Jersey – New Jersey Medical School
Ruchika Mohla
Affiliation:
University of Medicine & Dentistry of New Jersey – New Jersey Medical School
Allan Siegel
Affiliation:
University of Medicine & Dentistry of New Jersey – New Jersey Medical School
Charles S. Cleeland
Affiliation:
University of Texas, M. D. Anderson Cancer Center
Michael J. Fisch
Affiliation:
University of Texas, M. D. Anderson Cancer Center
Adrian J. Dunn
Affiliation:
University of Hawaii, Manoa
Get access

Summary

The term “sickness behavior” refers to a series of behavioral and physiological changes that occur after exposure to an inflammatory or infectious agent, or after administration of recombinant proinflammatory cytokines. Symptoms of sickness behavior include social withdrawal, anhedonia, cognitive impairment, anorexia, fever, and other symptoms. Behavioral changes associated with sickness behavior are transient in nature and serve adaptive purposes that help the individual mount an effective immune response.

Considerable attention has focused on the role of centrally acting cytokines in mediating sickness behavior. As might be expected, abnormal increases in cytokines appear to result in psychopathological outcomes. Indeed, sickness behavior and clinical depression (among other psychiatric disturbances) are evident in patients receiving cytokine therapy. Increased proinflammatory cytokine activity has been implicated in the etiology of depression, schizophrenia, and other psychiatric disorders.

Cancer-related symptoms are strikingly similar to the symptoms associated with cytokine-induced sickness behavior. On the basis of this observation and coupled with evidence that behavioral disturbances in patients with cancer may occur coincident with abnormal increases in proinflammatory cytokines, it has been suggested that common cytokine-related signaling pathways underlie sickness-related and cancer-related symptoms. In this chapter, we will discuss similarities between cancer-related symptoms and sickness behavior, and we will examine potential common mediators and mechanisms, including proinflammatory cytokines and subsequent interactions with neurotransmitter and molecular signaling pathways.

Cancer-related symptoms

Cancer-related symptoms refer to physical and psychiatric manifestations produced by the disease process or treatment (including chemotherapy, radiotherapy, immunotherapy, and surgical procedures). Cancer-related symptoms may be categorized as physical, cognitive, or affective.

Type
Chapter
Information
Cancer Symptom Science
Measurement, Mechanisms, and Management
 , pp. 8 - 17
Publisher: Cambridge University Press
Print publication year: 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Dantzer, R, Aubert, A, Bluthé, RM, et al. Mechanisms of the behavioural effects of cytokines. Adv Exp Med Biol 461:83–105, 1999.CrossRefGoogle ScholarPubMed
Raison, CL, Demetrashvili, M, Capuron, L, Miller, AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19(2):105–123, 2005.CrossRefGoogle ScholarPubMed
Müller, N, Schwarz, MJ. Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders. Expert Rev Neurother 6(7):1017–1038, 2006.CrossRefGoogle ScholarPubMed
Lee, BN, Dantzer, R, Langley, KE, et al. A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation 11(5):279–292, 2004.CrossRefGoogle ScholarPubMed
Kurzrock, R. Cytokine deregulation in cancer. Biomed Pharmacother 55(9–10):543–547, 2001.CrossRefGoogle Scholar
Cleeland, CS, Bennett, GJ, Dantzer, R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism?Cancer 97(11):2919–2925, 2003.CrossRefGoogle ScholarPubMed
Cleeland, CS. Cancer-related symptoms. Semin Radiat Oncol 10(3):175–190, 2000.CrossRefGoogle ScholarPubMed
Cleeland, CS, Mendoza, TR, Wang, XS, et al. Assessing symptom distress in cancer patients: the M. D. Anderson Symptom Inventory. Cancer 89(7):1634–1646, 2000.3.0.CO;2-V>CrossRefGoogle Scholar
Portenoy, RK, Thaler, HT, Kornblith, AB, et al. Symptom prevalence, characteristics and distress in a cancer population. Qual Life Res 3(3):183–189, 1994.CrossRefGoogle Scholar
Miaskowski, C, Aouizerat, BE. Is there a biological basis for the clustering of symptoms?Semin Oncol Nurs 23(2):99–105, 2007.CrossRefGoogle Scholar
Chen, ML, Tseng, HC. Symptom clusters in cancer patients. Support Care Cancer 14(8):825–830, 2006.CrossRefGoogle ScholarPubMed
Besedovsky, H, del Rey, A, Sorkin, E, Da Prada, M, Burri, R, Honegger, C. The immune response evokes changes in brain noradrenergic neurons. Science 221(4610):564–566, 1983.CrossRefGoogle ScholarPubMed
Zalcman, S, Shanks, N, Anisman, H. Time-dependent variations of central norepinephrine and dopamine following antigen administration. Brain Res 557(1–2):69–76, 1991.CrossRefGoogle ScholarPubMed
Williams, JM, Peterson, RG, Shea, PA, Schmedtje, JF, Bauer, DC, Felten, DL. Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune systems. Brain Res Bull 6(1):83–94, 1981.CrossRefGoogle ScholarPubMed
Nance, DM, Hopkins, DA, Bieger, D. Re-investigation of the innervation of the thymus gland in mice and rats. Brain Behav Immun 1(2):134–147, 1987.CrossRefGoogle ScholarPubMed
Nance, DM, Sanders, VM. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav Immun 21(6):736–745, 2007.CrossRefGoogle Scholar
Dantzer, R. Cytokine-induced sickness behavior: where do we stand?Brain Behav Immun 15(1):7–24, 2001.CrossRefGoogle ScholarPubMed
Layé, S, Parnet, P, Goujon, E, Dantzer, R. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Res Mol Brain Res 27(1):157–162, 1994.CrossRefGoogle Scholar
Rivest, S. Molecular insights on the cerebral innate immune system. Brain Behav Immun 17(1):13–19, 2003.CrossRefGoogle ScholarPubMed
Swiergiel, AH, Smagin, GN, Johnson, LJ, Dunn, AJ. The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1-receptor antagonist (IL-1ra). Brain Res 776(1–2):96–104, 1997.CrossRefGoogle Scholar
Rich, T, Innominato, PF, Boerner, J, et al. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res 11(5):1757–1764, 2005.CrossRefGoogle ScholarPubMed
Dunn, AJ. Effects of cytokines and infections on brain neurochemistry. In: Ader, R, Felten, DL, Cohen, N, eds. Psychoneuroimmunology. San Diego: Academic Press, 2001:649–686.Google Scholar
Yirmiya, R. Endotoxin produces a depressive-like episode in rats. Brain Res 711(1–2):163–174, 1996.CrossRefGoogle ScholarPubMed
Asarian, L, Langhans, W. Current perspectives on behavioural and cellular mechanisms of illness anorexia. Int Rev Psychiatry 17(6):451–459, 2005.CrossRefGoogle ScholarPubMed
Merali, Z, Brennan, K, Brau, P, Anisman, H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology (Berl) 165(4):413–418, 2003.CrossRefGoogle ScholarPubMed
Plata-Salamán, CR. Cytokines and feeding. Int J Obes Relat Metab Disord 25(Suppl 5):S48–S52, 2001.CrossRefGoogle Scholar
Kent, S, Bret-Dibat, JL, Kelley, KW, Dantzer, R. Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci Biobehav Rev 20(1):171–175, 1996.CrossRefGoogle ScholarPubMed
Zubareva, OE, Krasnova, IN, Abdurasulova, IN, Bluthé, RM, Dantzer, R, Klimenko, VM. Effects of serotonin synthesis blockade on interleukin-1 beta action in the brain of rats. Brain Res 915(2):244–247, 2001.CrossRefGoogle ScholarPubMed
Swiergiel, AH, Dunn, AJ. Lack of evidence for a role of serotonin in interleukin-1-induced hypophagia. Pharmacol Biochem Behav 65(3):531–537, 2000.CrossRefGoogle ScholarPubMed
Plata-Salamán, CR, Sonti, G, Borkoski, JP, Wilson, CD, French-Mullen, JM. Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Physiol Behav 60(3):867–875, 1996.CrossRefGoogle ScholarPubMed
Sakić, B, Gauldie, J, Denburg, JA, Szechtman, H.Behavioral effects of infection with IL-6 adenovector. Brain Behav Immun 15(1):25–42, 2001.CrossRefGoogle ScholarPubMed
Weingarten, HP. Cytokines and food intake: the relevance of the immune system to the student of ingestive behavior. Neurosci Biobehav Rev 20(1):163–170, 1996.CrossRefGoogle ScholarPubMed
Okamoto, T. NSAID zaltoprofen improves the decrease in body weight in rodent sickness behavior models: proposed new applications of NSAIDs (Review). Int J Mol Med 9(4):369–372, 2002.Google Scholar
Sharpless, NE, O'Brien, WA, Verdin, E, Kufta, CV, Chen, IS, Dubois-Dalcq, M. Human immunodeficiency virus type 1 tropism for brain microglial cells is determined by a region of the env glycoprotein that also controls macrophage tropism. J Virol 66(4):2588–2593, 1992.Google ScholarPubMed
Barak, O, Weidenfeld, J, Goshen, I, Ben-Hur, T, Taylor, AN, Yirmiya, R. Intracerebral HIV-1 glycoprotein 120 produces sickness behavior and pituitary-adrenal activation in rats: role of prostaglandins. Brain Behav Immun 16(6):720–735, 2002.CrossRefGoogle ScholarPubMed
Barak, O, Goshen, I, Ben-Hur, T, Weidenfeld, J, Taylor, AN, Yirmiya, R. Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120. Brain Res 933(2):98–108, 2002.CrossRefGoogle ScholarPubMed
Glowa, JR, Panlilio, LV, Brenneman, , Gozes, I, Fridkin, M, Hill, JM. Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist. Brain Res 570(1–2):49–53, 1992.CrossRefGoogle ScholarPubMed
Opp, MR, Rady, PL, Hughes, TK, Cadet, P, Tyring, SK, Smith, EM. Human immunodeficiency virus envelope glycoprotein 120 alters sleep and induces cytokine mRNA expression in rats [published errata appear in Am J Physiol 1996 Aug;271(2 Pt 2):section R following table of contents and 1996 Dec;271(6 Pt 3):section R following table of contents]. Am J Physiol 270(5 Pt 2):R963–R970, 1996.Google Scholar
Pugh, CR, Johnson, JD, Martin, D, Rudy, JW, Maier, SF, Watkins, LR. Human immunodeficiency virus-1 coat protein gp120 impairs contextual fear conditioning: a potential role in AIDS related learning and memory impairments. Brain Res 861(1):8–15, 2000.CrossRefGoogle ScholarPubMed
Capuron, L, Ravaud, A, Miller, AH, Dantzer, R. Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav Immun 18(3):205–213, 2004.CrossRefGoogle ScholarPubMed
Wood, LJ, Nail, LM, Perrin, NA, Elsea, CR, Fischer, A, Druker, BJ. The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior-like symptoms in a mouse model of cancer chemotherapy-related symptoms. Biol Res Nurs 8(2):157–169, 2006.CrossRefGoogle Scholar
Brebner, K, Hayley, S, Zacharko, R, Merali, Z, Anisman, H. Synergistic effects of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha: central monoamine, corticosterone, and behavioral variations. Neuropsychopharmacology 22(6):566–580, 2000.CrossRefGoogle ScholarPubMed
Dunn, AJ, Swiergiel, AH. The reductions in sweetened milk intake induced by interleukin-1 and endotoxin are not prevented by chronic antidepressant treatment. Neuroimmunomodulation 9(3):163–169, 2001.CrossRefGoogle Scholar
Larson, SJ, Romanoff, RL, Dunn, AJ, Glowa, JR. Effects of interleukin-1beta on food-maintained behavior in the mouse. Brain Behav Immun 16(4):398–410, 2002.CrossRefGoogle ScholarPubMed
Kent, S, Rodriguez, F, Kelley, KW, Dantzer, R. Reduction in food and water intake induced by microinjection of interleukin-1 beta in the ventromedial hypothalamus of the rat. Physiol Behav 56(5):1031–1036, 1994.CrossRefGoogle ScholarPubMed
Larson, SJ, Dunn, AJ. Behavioral effects of cytokines. Brain Behav Immun 15(4):371–387, 2001.CrossRefGoogle ScholarPubMed
Nakajima, A, Yamada, K, Nagai, T, et al. Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. J Neurosci 24(9):2212–2225, 2004.CrossRefGoogle ScholarPubMed
Zalcman, S, Green-Johnson, JM, Murray, L, et al. Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res 643(1–2):40–49, 1994.CrossRefGoogle ScholarPubMed
Song, C, Merali, Z, Anisman, H. Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 88(3):823–836, 1999.CrossRefGoogle ScholarPubMed
Zacharko, RM, Zalcman, S, Macneil, G, Andrews, M, Mendella, PD, Anisman, H. Differential effects of immunologic challenge on self-stimulation from the nucleus accumbens and the substantia nigra. Pharmacol Biochem Behav 58(4):881–886, 1997.CrossRefGoogle ScholarPubMed
Hebb, AL, Zacharko, RM, Anisman, H. Self-stimulation from the mesencephalon following intraventricular interleukin-2 administration. Brain Res Bull 45(6):549–556, 1998.CrossRefGoogle ScholarPubMed
Miguelez, M, Lacasse, M, Kentner, AC, Rizk, I, Fouriezos, G, Bielajew, C. Short- and long-term effects of interleukin-2 on weight, food intake, and hedonic mechanisms in the rat. Behav Brain Res 154(2):311–319, 2004.CrossRefGoogle Scholar
Anisman, H, Kokkinidis, L, Merali, Z. Interleukin-2 decreases accumbal dopamine efflux and responding for rewarding lateral hypothalamic stimulation. Brain Res 731(1–2):1–11, 1996.CrossRefGoogle ScholarPubMed
Lapchak, PA. A role for interleukin-2 in the regulation of striatal dopaminergic function. Neuroreport 3(2):165–168, 1992.CrossRefGoogle ScholarPubMed
Petitto, JM, McCarthy, DB, Rinker, CM, Huang, Z, Getty, T. Modulation of behavioral and neurochemical measures of forebrain dopamine function in mice by species-specific interleukin-2. J Neuroimmunol 73(1–2):183–190, 1997.CrossRefGoogle ScholarPubMed
Ye, JH, Tao, L, Zalcman, SS. Interleukin-2 modulates N-methyl-D-aspartate receptors of native mesolimbic neurons. Brain Res 894(2):241–248, 2001.CrossRefGoogle ScholarPubMed
Hanisch, UK, Neuhaus, J, Rowe, W, et al. Neurotoxic consequences of central long-term administration of interleukin-2 in rats. Neuroscience 79(3):799–818, 1997.CrossRefGoogle ScholarPubMed
Zalcman, S, Murray, L, Dyck, DG, Greenberg, AH, Nance, DM. Interleukin-2 and -6 induce behavioral-activating effects in mice. Brain Res 811(1–2):111–121, 1998.CrossRefGoogle ScholarPubMed
Nisticò, G, Sarro, G. Behavioral and electrocortical spectrum power effects after microinfusion of lymphokines in several areas of the rat brain. Ann N Y Acad Sci 621:119–134, 1991.CrossRefGoogle ScholarPubMed
Araujo, DM, Lapchak, PA, Collier, B, Quirion, R. Localization of interleukin-2 immunoreactivity and interleukin-2 receptors in the rat brain: interaction with the cholinergic system. Brain Res 498(2):257–266, 1989.CrossRefGoogle ScholarPubMed
Lacosta, S, Merali, Z, Anisman, H. Influence of acute and repeated interleukin-2 administration on spatial learning, locomotor activity, exploratory behaviors, and anxiety. Behav Neurosci 113(5):1030–1041, 1999.CrossRefGoogle ScholarPubMed
Petitto, JM, McNamara, RK, Gendreau, PL, Huang, Z, Jackson, AJ. Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion. J Neurosci Res 56(4):441–446, 1999.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Deimling, GT, Kahana, B, Bowman, KF, Schaefer, ML. Cancer survivorship and psychological distress in later life. Psychooncology 11(6):479–494, 2002.CrossRefGoogle ScholarPubMed
McHutchison, JG, Gordon, SC, Schiff, ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 339(21):1485–1492, 1998.CrossRefGoogle ScholarPubMed
Stefanski, V, Ben-Eliyahu, S. Social confrontation and tumor metastasis in rats: defeat and beta-adrenergic mechanisms. Physiol Behav 60(1):277–282, 1996.CrossRefGoogle ScholarPubMed
Petitto, JM, Lysle, DT, Gariepy, JL, Lewis, MH. Association of genetic differences in social behavior and cellular immune responsiveness: effects of social experience. Brain Behav Immun 8(2):111–122, 1994.CrossRefGoogle ScholarPubMed
Avitsur, R, Stark, JL, Dhabhar, FS, Sheridan, JF. Social stress alters splenocyte phenotype and function. J Neuroimmunol 132(1–2):66–71, 2002.CrossRefGoogle ScholarPubMed
Siegel, A, Roeling, TA, Gregg, TR, Kruk, MR. Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev 23(3):359–389, 1999.CrossRefGoogle ScholarPubMed
Siegel, A. The neurobiology of aggression and rage. Boca Raton: CRC Press, 2005.Google Scholar
Hassanain, M, Zalcman, S, Bhatt, S, Siegel, A. Interleukin-1 beta in the hypothalamus potentiates feline defensive rage: role of serotonin-2 receptors. Neuroscience 120(1):227–233, 2003.CrossRefGoogle ScholarPubMed
Hassanain, M, Bhatt, S, Zalcman, S, Siegel, A. Potentiating role of interleukin-1beta (IL-1beta) and IL-1beta type 1 receptors in the medial hypothalamus in defensive rage behavior in the cat. Brain Res 1048(1–2):1–11, 2005.CrossRefGoogle ScholarPubMed
Zalcman, SS, Siegel, A. The neurobiology of aggression and rage: role of cytokines. Brain Behav Immun 20(6):507–514, 2006.CrossRefGoogle ScholarPubMed
Bhatt, S, Zalcman, S, Hassanain, M, Siegel, A. Cytokine modulation of defensive rage behavior in the cat: role of GABAA and interleukin-2 receptors in the medial hypothalamus. Neuroscience 133(1):17–28, 2005.CrossRefGoogle ScholarPubMed
Bhatt, S, Siegel, A. Potentiating role of interleukin 2 (IL-2) receptors in the midbrain periaqueductal gray (PAG) upon defensive rage behavior in the cat: role of neurokinin NK(1) receptors. Behav Brain Res 167(2):251–260, 2006.CrossRefGoogle ScholarPubMed
Ottenweller, JE, Natelson, BH, Gause, WC, et al. Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue. Physiol Behav 63(5):795–801, 1998.CrossRefGoogle ScholarPubMed
Sheng, WS, Hu, S, Lamkin, A, Peterson, PK, Chao, CC. Susceptibility to immunologically mediated fatigue in C57BL/6 versus Balb/c mice. Clin Immunol Immunopathol 81(2):161–167, 1996.CrossRefGoogle ScholarPubMed
Glaser, R, Padgett, DA, Litsky, ML, et al. Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer. Brain Behav Immun 19(2):91–103, 2005.CrossRefGoogle ScholarPubMed
Nadjar, A, Bluthé, RM, May, MJ, Dantzer, R, Parnet, P. Inactivation of the cerebral NFkappaB pathway inhibits interleukin-1beta-induced sickness behavior and c-Fos expression in various brain nuclei. Neuropsychopharmacology 30(8):1492–1499, 2005.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org 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 saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ 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.

Available formats
×

Save book to Dropbox

To save content items to your account, please 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 account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please 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 account. Find out more about saving content to Google Drive.

Available formats
×