Skip to main content Accessibility help
×
Home

Follicular structures of cows with cystic ovarian disease present altered expression of cytokines

  • Antonela F. Stassi (a1), Natalia C. Gareis (a1) (a2), Belkis E. Marelli (a1) (a2), Valentina Matiller (a1) (a2), Cristian J.M. Leiva (a1), Florencia Rey (a1) (a2), Hugo H. Ortega (a1) (a2), Natalia R. Salvetti (a1) (a2) and M. Eugenia Baravalle (a1)...

Summary

Ovulation is considered an inflammatory, cytokine-mediated event. Cytokines, which are recognized as growth factors with immunoregulatory properties, are involved in many cellular processes at the ovarian level. In this sense, cytokines affect fertility and are involved in the development of different ovarian disorders such as bovine cystic ovarian disease (COD). Because it has been previously demonstrated that ovarian cells represent both sources and targets of cytokines, the aim of this study was to examine the expression of several cytokines, including IL-1β, IL-1RA, IL-1RI, IL-1RII, IL-4 and IL-8, in ovarian follicular structures from cows with spontaneous COD. The protein expression of these cytokines was evaluated by immunohistochemistry. Additionally, IL-1β, IL-4 and IL-8 concentrations in follicular fluid (FF) and serum were determined by enzyme-linked immunosorbent assay (ELISA). In granulosa and theca cells, IL-1RI, IL-1RII, IL-1RA and IL-4 expression levels were higher in cystic follicles than in the control dominant follicles. The serum and FF concentrations of IL-1β and IL-4 showed no differences between groups, whereas IL-8 concentration was detected only in FF of cysts from cows with COD. The FF and serum concentrations of IL-1β and IL-8 showed no significant differences, whereas IL-4 concentration was higher in FF than in serum in both the control and COD groups. These results evidenced an altered expression of cytokines in ovaries of cows with COD that could contribute to the pathogenesis of this disease.

Copyright

Corresponding author

Address for correspondence: María Eugenia Baravalle. ICiVet-Litoral, Universidad Nacional del Litoral – CONICET, R.P. Kreder 2805. (3080) Esperanza, Santa Fe, Argentina. Tel: +54 3496 420639. Fax: +54 3496 426304. E-mail: ebaravalle@live.com.ar

References

Hide All
Akdis, M, Aab, A, Altunbulakli, C, Azkur, K, Costa, RA, Crameri, R, et al. (2016) Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol 138, 9841010.
Amweg, AN, Salvetti, NR, Stangaferro, ML, Paredes, AH, Lara, HH, Rodríguez, FM and Ortega, HH (2013) Ovarian localization of 11β-hydroxysteroid dehydrogenase (11βHSD): Effects of ACTH stimulation and its relationship with bovine cystic ovarian disease. Domest Anim Endocrinol 45, 126–40.
Arend, WP (2002) The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 13, 323–40.
Baravalle, ME, Stassi, AF, Velázquez, MML, Belotti, EM, Rodríguez, FM, Ortega, HH and Salvetti, NR (2015) Altered expression of pro-inflammatory cytokines in ovarian follicles of cows with cystic ovarian disease. J Comp Pathol 153, 116–30.
Bartolomé, JA, Thatcher, WW, Melendez, P, Risco, CA and Archbald, LF (2005) Strategies for the diagnosis and treatment of ovarian cysts in dairy cattle. J Am Vet Med Assoc 227, 1409–14.
Belayet, HM, Kanayama, N, Khatun, S, Asahina, T, Okada, Y, Kitamura, K, Kobayashi, T and Terao, T (2000) Pharmacologic doses of interleukin 8 suppositories induce follicular maturation in rabbits. Cytokine 12, 361–7.
Bello, NM, Steibel, JP and Pursley, JR (2006) Optimizing ovulation to first GnRH improved outcomes to each hormonal injection of ovsynch in lactating dairy cows. J Dairy Sci 89, 3413–24.
Bonder, CS, Dickensheets, HL, Finlay-Jones, JJ, Donnelly, RP and Hart, PH (1998) Involvement of the IL-2 receptor gamma-chain (gammac) in the control by IL-4 of human monocyte and macrophage proinflammatory mediator production. J Immunol 160, 4048–56.
Bonecchi, R, Garlanda, C, Mantovani, A and Riva, F (2016) Cytokine decoy and scavenger receptors as key regulators of immunity and inflammation. Cytokine 87, 37–45.
Bornstein, SR, Rutkowski, H and Vrezas, I (2004) Cytokines and steroidogenesis. Mol Cell Endocrinol 215, 135–41.
Brännström, M (2004) Potential role of cytokines in ovarian physiology: the case for interleukin-1. In: The Ovary, 2nd edn, Leung, PCK, Adashi, EY, eds, Elsevier Academic Press, Vancouver, pp. 261–71.
Brännström, M, Wang, L and Norman, RJ (1993) Ovulatory effect of interleukin-1 beta on the perfused rat ovary. Endocrinology 132, 399404.
Braw-Tal, R and Yossefi, S (1997) Studies in-vivo and in-vitro on the initiation of follicle growth in the bovine ovary. J Reprod Fertil 109, 165–71.
Bukulmez, O and Arici, A (2000) Leukocytes in ovarian function. Hum Reprod 6, 115.
Büscher, U, Chen, FC, Kentenich, H and Schmiady, H (1999) Cytokines in the follicular fluid of stimulated and non-stimulated human ovaries; is ovulation a suppressed inflammatory reaction? Hum Reprod 14, 162–6.
Caillaud, M, Duchamp, G and Gérard, N (2005) In vivo effect of interleukin-1beta and interleukin-1RA on oocyte cytoplasmic maturation, ovulation, and early embryonic development in the mare. Reprod Biol Endocrinol 3, 19.
Cattaneo, L, Signorini, ML, Bertoli, J, Bartolomé, JA, Gareis, NC, Díaz, PU, Bo, GA and Ortega, HH (2014) Epidemiological description of cystic ovarian disease in Argentine dairy herds: risk factors and effects on the reproductive performance of lactating cows. Reprod Domest Anim 49, 1028–33.
Chun, SY, Eisenhauer, KM, Kubo, M and Hsueh, AJ (1995) Interleukin-1 beta suppresses apoptosis in rat ovarian follicles by increasing nitric oxide production. Endocrinology 136, 3120–7.
Colotta, F, Re, F, Muzio, M, Polentarutti, N, Minty, A, Caput, D, Ferrara, P and Mantovani, A (1994) Interleukin-13 induces expression and release of interleukin-1 decoy receptor in human polymorphonuclear cells. J Biol Chem 269, 12403–6.
Colotta, F, Re, F, Muzio, M, Bertini, R, Polentarutti, N, Sironi, M, Giri, JG, Dower, SK, Sims, JE and Mantovani, A (1993) Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 61, 472–5.
Colotta, F, Saccani, S, Giri, JG, Dower, SK, Sims, JE, Introna, M and Mantovani, A (1996) Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes. J Immunol 156, 2534–41.
Dang, X, Zhu, Q, He, Y, Wang, Y, Lu, Y, Li, X, Qi, J, Wu, H and Sun, Y (2017) IL-1β up-regulates StAR and progesterone production through the ERK1/2-and p38-mediated CREB signaling pathways in human granulosa-lutein cells. Endocrinology 158, 3281–91.
Daun, JM, Ball, RW, Burger, HR and Cannon, JG (1999) Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo . J Leukoc Biol 65, 863–6.
De, M, Sanford, T and Wood, G (1992) Interleukin-1, Interleukin-6, and tumor necrosis factor-α are produced in the mouse uterus during the estrous cycle and are induced by estrogen and progesterone. Dev Biol 151, 297305.
Dembic, Z (2015) Cytokines of the Immune System: Interleukins. In: The Cytokines of the Immune System 6, 143239.
Deshpande, R, Chang, M, Chapman, J and Michael, S (2000) Alteration of cytokine production in follicular cystic ovaries induced in mice by neonatal estradiol injection. Am J Reprod Immunol 44, 80–8.
Díaz, PU, Stangaferro, ML, Gareis, NC, Silvia, W, Matiller, V, Salvetti, NR, Rey, F, Barberis, F, Cattaneo, L and Ortega, HH (2015) Characterization of persistent follicles induced by prolonged treatment with progesterone in dairy cows: an experimental model for the study of ovarian follicular cysts. Theriogenology 84, 1149–60.
Dickensheets, HL and Donnelly, RP (1997) IFN-gamma and IL-10 inhibit induction of IL-1 receptor type I and type II gene expression by IL-4 and IL-13 in human monocytes. J Immunol 159, 6226–33.
Dinarello, CA (2013) Overview of the interleukin-1 family of ligands and receptors. Semin Immunol 25, 389–93.
Ebejer, K and Calleja-Agius, J (2013) The role of cytokines in polycystic ovarian syndrome. Gynecol Endocrinol 29, 536–40.
Ellman, C, Corbett, JA, Misko, TP, McDaniel, M and Beckerman, KP (1993) Nitric oxide mediates interleukin-1-induced cellular cytotoxicity in the rat ovary. A potential role for nitric oxide in the ovulatory process. J Clin Invest 92, 3053–6.
Field, SL, Dasgupta, T, Cummings, M and Orsi, NM (2014) Cytokines in ovarian folliculogenesis, oocyte maturation and luteinisation. Mol ReprodDev 81, 284314.
Gaafar, TM, Hanna, MOF, Hammady, MR, Amr, HM, Osman, OM, Nasef, A and Osman, AM (2014) Evaluation of cytokines in follicular fluid and their effect on fertilization and pregnancy outcome. Immunol Invest 43, 572–84.
Garcia-Velasco, JA and Arici, A (1998) Chemokines and human reproduction. Fertil Steril 71, 983–93.
Garlanda, C, Dinarello, CA and Mantovani, A (2013) The interleukin-1 family: back to the future. Immunity 39, 1003–18.
Garverick, HA (1997) Ovarian follicular cysts in dairy cows. J Dairy Sci 80, 9951004.
Hatler, TB, Hayes, SH, Ray, DL, Reames, PS and Silvia, WJ (2008) Effect of subluteal concentrations of progesterone on luteinizing hormone and ovulation in lactating dairy cows. Vet J 177, 360–8.
Hurwitz, A, Loukides, J, Ricciarelli, E, Botero, L, Katz, E, McAllister, JM, Garcia, JE, Rohan, R, Adashi, EY and Hernandez, ER (1992) Human intraovarian interleukin-1 (IL1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL1, its receptor, and its receptor antagonist. J Clin Invest 89, 17461754.
Hurwitz, A, Dushnik, M, Solomon, H, Ben-Chetrit, A, Finci-Yeheskel, Z, Milwidsky, A, Mayer, M, Adashi, EY and Yagel, S (1993) Cytokine-mediated regulation of rat ovarian function: interleukin-1 stimulates the accumulation of a 92-kilodalton gelatinase. Endocrinology 132, 2709–14.
Isobe, N, Kitabayashi, M and Yoshimura, Y (2005) Microvascular distribution and vascular endothelial growth factor expression in bovine cystic follicles. Domest Anim Endocrinol 29, 634–45.
Isobe, N, Kitabayashi, M and Yoshimura, Y (2008) Expression of vascular endothelial growth factor receptors in bovine cystic follicles. Reprod Domest Anim 43, 267–71.
Jiemtaweeboon, S, Shirasuna, K, Nitta, A, Kobayashi, A, Schuberth, H, Shimizu, T and Miyamoto, A (2011) Evidence that polymorphonuclear neutrophils infiltrate into the developing corpus luteum and promote angiogenesis with interleukin-8 in the cow. Reprod Biol Endocrinol 8, 979.
Kalliolias, GD, Gordon, RA and Ivashkiv, LB (2010) Suppression of TNF-alpha and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27. J Immunol 185, 7047–56.
Kitaya, K and Yamada, H (2011) Pathophysiological roles of chemokines in human reproduction: an overview. Am J Reprod Immunol 65, 449–59.
Koch, AE, Polverini, PJ, Kunkel, SL, Harlow, LA, DiPietro, LA, Elner, VM, Elner, SG and Strieter, RM (1992) Interleukin 8 as a macrophage derived mediator of angiogenesis. Science 258, 1798–801.
Kuhn, PH, Marjaux, E, Imhof, A, De Strooper, B, Haass, C and Lichtenthaler, SF (2007) Regulated intramembrane proteolysis of the intereukin-1 receptor II by alpha-, beta-, and gamma-secretase. J Biol Chem 282, 11982–95.
Leo, CP, Pisarska, MD and Hsueh, AJ (2001) DNA array analysis of changes in preovulatory gene expression in the rat ovary. Biol Reprod 65, 269–76.
Li, A, Varney, ML, Valasek, J, Godfrey, M, Dave, BJ and Singh, RK (2005) Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis 8, 6371.
Lorenzen, I, Lokau, J, Düsterhöft, S, Trad, A, Garbers, C, Scheller, J, Rose-John, S and Grötzinger, J (2012) The membrane-proximal domain of A disintegrin and metalloprotease 17 (ADAM17) is responsible for recognition of the interleukin-6 receptor and interleukin-1 receptor II. FEBS Lett 586, 1093–100.
Marelli, BE, Díaz, PU, Salvetti, NR, Rey, F and Ortega, HH (2014) mRNA expression pattern of gonadotropin receptors in bovine follicular cysts. Biol Reprod 4, 276–81.
Matiller, V, Stangaferro, ML, Díaz, PU, Ortega, HH, Rey, F, Huber, E and Salvetti, NR (2014) Altered expression of transforming growth factor beta isoforms in bovine cystic ovarian disease. Reprod Domest Anim 49, 813–23.
Mu, Y, Liu, J, Wang, B, Wen, Q, Wang, J, Yan, J, Zhou, S, Ma, X and Cao, Y (2010) Interleukin 1 beta (IL-1β) promoter C [-511] T polymorphism but not C [+3953] T polymorphism is associated with polycystic ovary syndrome. Endocrine 37, 71–5.
Niu, Z, Ye, Y, Xia, L, Fengm, Y and Zhang, A (2017) Follicular fluid cytokine composition and oocyte quality of polycystic ovary syndrome patients with metabolic syndrome undergoing in vitro fertilization. Cytokine 91, 180–6.
Oakley, OR, Kim, H, El-Amouri, I, Lin, PC, Cho, J, Bani-Ahmad, M and Ko, C (2010) Periovulatory leukocyte infiltration in the rat ovary. Endocrinology 151, 4551–9.
Orsi, NM (2008) Cytokine networks in the establishment and maintenance of pregnancy. Hum Fertil 11, 222–30.
Orsi, NM and Tribe, RM (2008) Cytokine networks and the regulation of uterine function in pregnancyand parturition. Neuroendocrinology 20, 462–9.
Ortega, HH, Díaz, PU, Salvetti, NR, Hein, GJ, Marelli, BE, Rodríguez, FM, Stassi, AF and Rey, F (2016) Follicular cysts: a single sign and different diseases. a view from comparative medicine. Curr Pharm Des 22, 5634–45.
Ortega, HH, Rey, F, Velázquez, MML and Padmanabhan, V (2010) Developmental programming: effect of prenatal steroid excess on intraovarian components of insulin signaling pathway and related proteins in sheep. Biol Reprod 82, 1065–75.
Ou, HL, Sun, D, Peng, YC and Wu, YL (2016) Novel effects of the cyclooxygenase-2-selective inhibitor NS-398 on IL-1β-induced cyclooxygenase-2 and IL-8 expression in human ovarian granulosa cells. Innate Immun 22, 452–65.
Passos, JRS, Costa, JJN, da Cunha, EV, Silva, AWB, Ribeiro, RP, de Souza, GB, Barroso, PA, Dau, AM, Saraiva, MV, Gonçalves, PB, van den Hurk, R and Silva, JR (2016) Protein and messenger RNA expression of interleukin 1 system members in bovine ovarian follicles and effects of interleukin 1b on primordial follicle activation and survival in vitro . Domest Anim Endocrinol 54, 4859.
Peter, AT (2004) An update on cystic ovarian degeneration in cattle. Reprod Domest Anim 39, 17.
Probo, M, Comin, A, Mollo, A, Cairoli, F, Stradaioli, G and Veronesi, MC (2011) Reproductive performance of dairy cows with luteal or folicular ovarian cysts after treatment with buserelin. Anim Reprod Sci 127, 135–9.
Ranefall, P, Wester, K, Andersson, AC, Busch, C and Bengtsson, E (1998) Automatic quantification of immunohistochemically stained cell nuclei based on standard reference cells. Anal Cell Pathol 17, 111–23.
Rashid, N, Nigam, A, Saxena, P, Jain, SK and Wajid, S (2017) Association of IL-1β, IL-1Ra and FABP1 gene polymorphisms with the metabolic features of polycystic ovary syndrome. Inflamm Res 66, 621–36.
Re, F, Muzio, M, De Rossi, M, Polentarutti, N, Giri, JG, Mantovani, A and Colotta, F (1994) The type II ‘‘receptor’ as a decoy target for interleukin 1 in polymorphonuclear leukocytes: characterization of induction by dexamethasone and ligand binding properties of the released decoy receptor. J Exp Med 179, 739–43.
Re, F, Sironi, M, Muzio, M, Matteucci, C, Introna, M, Orlando, S, Penton-Rol, G, Dower, SK, Sims, JE, Colotta, F and Mantovani, A (1996) Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface ‘receptor’ with anti-interleukin-1 function. J Exp Med 183, 1841–50.
Richards, JS, Liu, Z and Shimada, M (2008) Immune-like mechanisms in ovulation. Trends Endocrinol Metab 19, 191–6.
Richards, JS and Pangas, SA (2010) The ovary: basic biology and clinical implications. J Clin Invest 120, 963–72.
Rizzo, A, Campanile, D, Mutinati, M, Minoia, G, Spedicato, M and Sciorsci, RL (2011) Epidural vs intramuscular administration of lecirelin, a GnRH analogue, for the resolution of follicular cysts in dairy cows. Anim Reprod Sci 126, 1922.
Rodgers, RJ and Irving-Rodgers, HF (2010) Morphological classification of bovine ovarian follicles. Reproduction 139, 309–18.
Salvetti, NR, Müller, LA, Acosta, JC, Gimeno, JE and Ortega, HH (2007) Estrogen receptors a and b and progesterone receptors in ovarian follicles of cows with cystic ovarian disease. Vet Pathol 44, 373–8.
Salvetti, NR, Stangaferro, ML, Palomar, MM, Alfaro, NS, Rey, F, Gimeno, EJ and Ortega, HH (2010) Cell proliferation and survival mechanisms underlying the abnormal persistence of folicular cysts in bovines with cystic ovarian disease induced by ACTH. Anim Reprod Sci 122, 98110.
Schadendorf, D, Moller, A, Algermissen, B, Worm, M, Sticherling, M and Czarnetzki, BM (1993) IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 151, 26672675.
Scherzer, WJ, Ruutiainen-Altman, KS, Putowski, LT, Kol, S, Adashi, EY and Rohan, RM (1996) Detection and in vivo hormonal regulation of rat ovarian type I and type II interleukin-I receptor mRNAs: increased expression during the periovulatory period. J Soc Gynecol Invest 3, 131–9.
Shimizu, T, Imamura, E, Magata, F, Murayama, C and Miyamoto, A (2013) Interleukin-8 stimulates progesterone production via the MEK pathway in ovarian theca cells. Mol Cell Biochem 374, 157–61.
Shimizu, T, Kaji, A, Murayama, C, Magata, F, Shirasuna, K, Wakamiya, K, Okuda, K and Miyamoto, A (2012) Effects of interleukin-8 on estradiol and progesterone production by bovine granulosa cells from large follicles and progesterone production by luteinizing granulosa cells in culture. Cytokine 57, 175–81.
Silvia, WJ, Alter, TB, Nugent, AM and Laranja da Fonseca, LF (2002) Ovarian follicular cysts in dairy cows: an abnormality in folliculogenesis. Domest Anim Endocrinol 23, 167–77.
Silvia, WJ, McGinnis, AS and Hatler, TB (2005) A comparison of adrenal gland function in lactating dairy cows with or without ovarian follicular cysts. Biol Reprod 5, 1929.
Sims, JE, Giri, JG and Dower, SK (1994) The two interleukin-1 receptors play different roles in IL-1 actions. Clin Immunol Immunopathol 72, 914.
Sirotkin, A (2011) Cytokines: signalling molecules controlling ovarian functions. Int J Biochem Cell Biol 43, 857–61.
Smith, DE, Hanna, R, Della Friend Moore, H, Chen, H, Farese, AM, MacVittie, TJ, Virca, GD and Sims, JE (2003) The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity 18, 8796.
Smolikova, K, Mlynarcikova, A and Scsukova, S (2012) Role of interleukins in the regulation of ovarian functions. Endocr Regul 46, 237–53.
Spriggs, MK, Nevens, PJ, Grabstein, K, Dower, SK, Cosman, D, Armitage, RJ and McMahan, CJ, Sims, JE (1992) Molecular characterization of the interleukin-1 receptor (IL-1R) on monocytes and polymorphonuclear cells. Cytokine 4, 90–5.
Stassi, AF, Baravalle, ME, Belotti, EM, Amweg, AN, Angeli, E, Velázquez, MML, Rey, F, Salvetti, NR and Ortega, HH (2018) Altered expression of IL-1β, IL-1RI, IL-1RII, IL-1RA and IL-4 could contribute to anovulation and follicular persistence in cattle. Theriogenology 110, 6173.
Stassi, AF, Baravalle, ME, Belotti, EM, Rey, F, Gareis, NC, Díaz, PU, Rodríguez, FM, Leiva, CJ, Ortega, HH and Salvetti, NR (2017) Altered expression of cytokines IL-1α, IL-6, IL-8 and TNF-α in bovine follicular persistence. Theriogenology 97, 104–12.
Terranova, P and Rice, V (1997) Cytokine involvement in ovarian processes. Am J Reprod Immunol 37, 5063.
Ujioka, T, Matsukawa, A, Tanaka, N, Matsuura, K, Yoshinaga, M and Okamura, H (1998) Interleukin-8 as an essential factor in the human chorionic gonadotropin-induced rabbit ovulatory process: interleukin-8 induces neutrophil accumulation and activation in ovulation. Biol Reprod 58, 526–30.
Vanholder, T, Opsomer, G and de Kruif, A (2006) Etiology and pathogenesis of cystic ovarian follicles in dairy cattle: a review. Reprod Nut Dev 46, 105–19.
Volpert, OV, Fong, T, Koch, AE, Peterson, JD, Waltenbaugh, C, Tepper, RI and Bouck, NP (1998) Inhibition of angiogenesis by interleukin 4. J Exp Med 188, 1039–46.
Wang, CJ, Zhou, ZG, Holmqvist, A, Zhang, H, Li, Y, Adell, G and Sun, XF (2009) Survivin expression quantified by Image Pro-Plus compared with visual assessment. Appl Immunohistochem Mol Morphol 17, 530–5.
Woods, AM and Judd, AM (2008) Interleukin-4 increases cortisol release and decreases adrenal androgen release from bovine adrenal cells. Domest Anim Endocrinol 34, 372–82.

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed