Issue
Pinealectomy alters IFN-γ and IL-10 levels in primary thymocyte culture of rats
Corresponding Author(s) : Zafer Sahin
Cellular and Molecular Biology,
Vol. 64 No. 14: Issue 14
Abstract
Melatonin, produced mainly by the pineal gland, has an immunomodulatory role. However, the effects of the pineal gland and/or melatonin on thymus cytokine levels such as interferon-gamma (IFN-γ), interleukin (IL)-4, and IL-10 are not well known. Twenty-one male Wistar rats (220-250 gr) were randomly divided into three groups (n=7): intact control, sham, and pinealectomy. Primary thymocyte cultures were prepared from each group and dispensed into well plates as Control, DMSO (or vehicle), Sham-pinealectomy, Pinealectomy, Pinealectomy+10µM melatonin, and Pinealectomy+100µM melatonin. IFN-γ, IL-4, and IL-10 concentrations were measured in the thymocytes (as nonstimulated and Concanavalin A-stimulated) after 24 h. IFN-γ levels significantly increased and IL-10 levels significantly decreased in both media prepared from pinealectomized rats. There was no significant difference between the groups in terms of IL-4. In the pinealectomy+10µM melatonin group, IFN-γ and IL-10 levels did not differ from the pinealectomy group. However, the dose of 100µM melatonin caused a decrease in levels of IFN-γ in both thymocyte media and an increase in the concentration of IL-10 in Concanavalin A-stimulated thymocytes. In conclusion, pineal gland and/or melatonin affect IFN-γ and IL-10 levels in the thymus gland.
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- Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 2000; 28:193–202.
- Carrillo-Vico A, Lardone PJ, Fernandez-Santos JM, Martin-Lacave I, Calvo JR, Karasek M, et al. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab 2005; 90:992–1000.
- Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, Carrascosa-Salmoral MP, et al. Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci 2007; 64:781–790.
- Reiter RJ. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol 1991; 79:153–8.
- Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186-95.
- Csaba G. The pineal regulation of the immune system: 40 years since the discovery. Acta Microbiol Immunol Hung 2013; 60:77-91.
- Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem 2002; 2:167–179.
- Skwarlo-Sonta K. Melatonin in immunity: comparative aspects. Neuroendocrinol Lett 2002; 23:61–66.
- Csaba G, Barath P. Morphological changes of thymus and the thyroid gland after postnatal extirpation of pineal body. Endocrinol Exp 1975; 9:59–67.
- Vaughan MK, Reiter RJ. Transient hypertrophy of the ventral prostate and coagulating glands and accelerated thymic involution following pinealectomy in the mouse. Tex Rep Biol Med 1971; 29: 579–586.
- Oner H, Kus I, Oner J, Ogeturk M, Ozan E, Ayar A. Possible effects of melatonin on thymus gland after pinealectomy in rats. Neuro Endocrinol Lett 2004; 25:115–118.
- Pozo D, Delgado M, Fernandez-Santos JM, Calvo JR, Gomariz RP, Martin-Lacave I, et al. Expression of the Mel1a-melatonin receptor mRNA in T and B subsets of lymphocytes from rat thymus and spleen. FASEB J 1997; 11:466–473.
- Rafii-El-Idrissi M, Calvo JR, Harmouch A, Garcia-Maurino S, Guerrero JM. Specific binding of melatonin by purified cell nuclei from spleen and thymus of the rat. J Neuroimmunol 1998; 86:190–197.
- Carrillo-Vico A, Garcia-Perganeda A, Naji L, Calvo J R, Romero MP, Guerrero JM. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci 2003; 60:2272–2278.
- Anderson G, Moore NC, Owen JJ, Jenkinson EJ. Cellular interactions in thymocyte development. Annu Rev Immunol 1996; 14:73–99.
- Rothenberg EV, Moore JE, Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol 2008; 8:9-21.
- Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74:5-17.
- Vahedi GC, Poholek A, Hand TW, Laurence A, Kanno Y, O'Shea JJ, et al. Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol Rev 2013; 252:24-40.
- Ren W, Liu G, Chen S, Yin J, Wang J, Tan B, et al. Melatonin signaling in T cells: Functions and applications. J Pineal Res 2017; 62,e12394.
- Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine 2005; 27:189–200.
- Canpolat S, Sandal S, Yilmaz B, Yasar A, Kutlu S, Baydas G, et al. Effects of pinealectomy and exogenous melatonin on serum leptin levels in male rat. Eur J Pharmacol 2001; 428:145-8.
- Oyama Y, Carpenter DO, Ueno S, Hayashi H, Tomiyoshi F. Methylmercury induces Ca2+-dependent hyperpolarization of mouse thymocytes. A flow-cytometric study using fluorescent dyes. Eur J Pharmacol 1995; 293:101–107.
- Sandal S, Yilmaz B, Godekmerdan A, Kelestimur H, Carpenter DO. Effects of PCBs 52 and 77 on Th1/Th2 balance in mouse thymocyte cell cultures. Immunopharmacol Immunotoxicol 2005; 27:601-613.
- Sandal S, Tuneva J, Yilmaz B, Carpenter DO. Effects of cholesterol and docosahexaenoic acid on cell viability and (Ca(2+))(i) levels in acutely isolated mouse thymocytes. Cell Biochem Funct 2009; 27:155-61.
- Elenkov IJ. Neurohormonal-cytokine interactions: Implications for inflammation, common human diseases and well-being Neurochem Int 2008; 52:40-51.
- Jimenez-Jorge S, Jimenez-Caliani AJ, Guerrero JM, Naranjo MC, Lardone PJ, Carrillo-Vico A, et al. Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal gland. J Pineal Res 2005; 39:77–83.
- Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 1993; 14:1–10.
- Sainz RM, Mayo JC, Uria H, Kotler M, Antolin I, Rodriguez C, et al. The pineal neurohormone melatonin prevents in vivo and in vitro apoptosis in thymocytes. J Pineal Res 1995; 19:178–188.
- Fabris N, Mocchegiani E, Provinciali M. Plasticity of neuro-endocrine-thymus interactions during aging-a minireview. Cell Mol Biol (Noisy-le-grand). 1997;43:529-41.
- Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, et al. Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 2007; 128:83–91.
- Garcia-Maurino S, Gonzalez-Haba MG, Calvo JR, Rafii-El-Idrissi M, Sanchez-Margalet V, Goberna R, et al. Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol 1997; 159:574-581.
- Miller SC, Pandi-Perumal SR, Esquifino AI, Cardinali DP, Maestroni GJ. The role of melatonin in immuno-enhancement: Potential application in cancer. Int J Exp Pathol 2006; 87:81–87.
- Park E, Chun HS. Melatonin Attenuates Manganese and Lipopolysaccharide-Induced Inflammatory Activation of BV2 Microglia. Neurochem Res 2017; 42:656-666.
- Petrovsky N, Harrsion LC. Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? J Immunol 1997; 158:5163-5168.
- Motilva V, Cabeza J, Alarcón de la Lastra C. New issues about melatonin and its effects on the digestive system. Curr Pharm Des 2001; 7: 909–931.
- Petrovsky N, Harrsion LC. Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? J Immunol 1997; 158:5163-5168.
- Raghavendra V, Singh V, Kulkarni SK, Agrewala JN. Melatonin enhances Th2 cell mediated immune responses: Lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Mol Cell Biochem 2001; 221:57-62.
- Yarilin AA, Belyakov IM. Cytokines in the thymus: production and biological effects. Curr Med Chem 2004; 11:447-64.
- Yan F, Mo X, Liu J, Ye S, Zeng X, Chen D. Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review). Mol Med Rep 2017; 16:7175-7184.
- Chemin K, Bohineust A, Dogniaux S, Tourret M., Guégan S., Miro F., et al. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J Immunol 2012; 189:2159-2168.
- Zlotnik A, Ransom J, Frank G, Fischer M, Howard M. Interleukin 4 is a growth factor for activated thymocytes: Possible role in T-cell ontogeny. Proc Natl Acad Sci USA 1987; 84:3856-3860.
- Meilin A, Sharabi Y, Shoham J. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium V. Proliferation regulating activities in supernatants of human thymic epithelial cell cultures. Int J Immunopharmacol 1997; 19:39-47.
- Barnes MJ, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity 2009; 31:401-411.
- Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 2009; 30:636-645.
- Mittal SK, Roche PA. Suppression of antigen presentation by IL-10. Curr Opin Immunol 2015; 34:22-27.
- Patel DD, Whichard LP, Radcliff G, Denning SM, Haynes BF. Characterization of human thymic epithelial cell surface antigens: phenotypic similarity of thymic epithelial cells to epidermal keratinocytes. J Clin Immunol 1995; 15:80-92.
References
Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 2000; 28:193–202.
Carrillo-Vico A, Lardone PJ, Fernandez-Santos JM, Martin-Lacave I, Calvo JR, Karasek M, et al. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab 2005; 90:992–1000.
Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, Carrascosa-Salmoral MP, et al. Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci 2007; 64:781–790.
Reiter RJ. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol 1991; 79:153–8.
Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186-95.
Csaba G. The pineal regulation of the immune system: 40 years since the discovery. Acta Microbiol Immunol Hung 2013; 60:77-91.
Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem 2002; 2:167–179.
Skwarlo-Sonta K. Melatonin in immunity: comparative aspects. Neuroendocrinol Lett 2002; 23:61–66.
Csaba G, Barath P. Morphological changes of thymus and the thyroid gland after postnatal extirpation of pineal body. Endocrinol Exp 1975; 9:59–67.
Vaughan MK, Reiter RJ. Transient hypertrophy of the ventral prostate and coagulating glands and accelerated thymic involution following pinealectomy in the mouse. Tex Rep Biol Med 1971; 29: 579–586.
Oner H, Kus I, Oner J, Ogeturk M, Ozan E, Ayar A. Possible effects of melatonin on thymus gland after pinealectomy in rats. Neuro Endocrinol Lett 2004; 25:115–118.
Pozo D, Delgado M, Fernandez-Santos JM, Calvo JR, Gomariz RP, Martin-Lacave I, et al. Expression of the Mel1a-melatonin receptor mRNA in T and B subsets of lymphocytes from rat thymus and spleen. FASEB J 1997; 11:466–473.
Rafii-El-Idrissi M, Calvo JR, Harmouch A, Garcia-Maurino S, Guerrero JM. Specific binding of melatonin by purified cell nuclei from spleen and thymus of the rat. J Neuroimmunol 1998; 86:190–197.
Carrillo-Vico A, Garcia-Perganeda A, Naji L, Calvo J R, Romero MP, Guerrero JM. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci 2003; 60:2272–2278.
Anderson G, Moore NC, Owen JJ, Jenkinson EJ. Cellular interactions in thymocyte development. Annu Rev Immunol 1996; 14:73–99.
Rothenberg EV, Moore JE, Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol 2008; 8:9-21.
Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74:5-17.
Vahedi GC, Poholek A, Hand TW, Laurence A, Kanno Y, O'Shea JJ, et al. Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol Rev 2013; 252:24-40.
Ren W, Liu G, Chen S, Yin J, Wang J, Tan B, et al. Melatonin signaling in T cells: Functions and applications. J Pineal Res 2017; 62,e12394.
Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine 2005; 27:189–200.
Canpolat S, Sandal S, Yilmaz B, Yasar A, Kutlu S, Baydas G, et al. Effects of pinealectomy and exogenous melatonin on serum leptin levels in male rat. Eur J Pharmacol 2001; 428:145-8.
Oyama Y, Carpenter DO, Ueno S, Hayashi H, Tomiyoshi F. Methylmercury induces Ca2+-dependent hyperpolarization of mouse thymocytes. A flow-cytometric study using fluorescent dyes. Eur J Pharmacol 1995; 293:101–107.
Sandal S, Yilmaz B, Godekmerdan A, Kelestimur H, Carpenter DO. Effects of PCBs 52 and 77 on Th1/Th2 balance in mouse thymocyte cell cultures. Immunopharmacol Immunotoxicol 2005; 27:601-613.
Sandal S, Tuneva J, Yilmaz B, Carpenter DO. Effects of cholesterol and docosahexaenoic acid on cell viability and (Ca(2+))(i) levels in acutely isolated mouse thymocytes. Cell Biochem Funct 2009; 27:155-61.
Elenkov IJ. Neurohormonal-cytokine interactions: Implications for inflammation, common human diseases and well-being Neurochem Int 2008; 52:40-51.
Jimenez-Jorge S, Jimenez-Caliani AJ, Guerrero JM, Naranjo MC, Lardone PJ, Carrillo-Vico A, et al. Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal gland. J Pineal Res 2005; 39:77–83.
Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 1993; 14:1–10.
Sainz RM, Mayo JC, Uria H, Kotler M, Antolin I, Rodriguez C, et al. The pineal neurohormone melatonin prevents in vivo and in vitro apoptosis in thymocytes. J Pineal Res 1995; 19:178–188.
Fabris N, Mocchegiani E, Provinciali M. Plasticity of neuro-endocrine-thymus interactions during aging-a minireview. Cell Mol Biol (Noisy-le-grand). 1997;43:529-41.
Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, et al. Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 2007; 128:83–91.
Garcia-Maurino S, Gonzalez-Haba MG, Calvo JR, Rafii-El-Idrissi M, Sanchez-Margalet V, Goberna R, et al. Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol 1997; 159:574-581.
Miller SC, Pandi-Perumal SR, Esquifino AI, Cardinali DP, Maestroni GJ. The role of melatonin in immuno-enhancement: Potential application in cancer. Int J Exp Pathol 2006; 87:81–87.
Park E, Chun HS. Melatonin Attenuates Manganese and Lipopolysaccharide-Induced Inflammatory Activation of BV2 Microglia. Neurochem Res 2017; 42:656-666.
Petrovsky N, Harrsion LC. Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? J Immunol 1997; 158:5163-5168.
Motilva V, Cabeza J, Alarcón de la Lastra C. New issues about melatonin and its effects on the digestive system. Curr Pharm Des 2001; 7: 909–931.
Petrovsky N, Harrsion LC. Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? J Immunol 1997; 158:5163-5168.
Raghavendra V, Singh V, Kulkarni SK, Agrewala JN. Melatonin enhances Th2 cell mediated immune responses: Lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Mol Cell Biochem 2001; 221:57-62.
Yarilin AA, Belyakov IM. Cytokines in the thymus: production and biological effects. Curr Med Chem 2004; 11:447-64.
Yan F, Mo X, Liu J, Ye S, Zeng X, Chen D. Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review). Mol Med Rep 2017; 16:7175-7184.
Chemin K, Bohineust A, Dogniaux S, Tourret M., Guégan S., Miro F., et al. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J Immunol 2012; 189:2159-2168.
Zlotnik A, Ransom J, Frank G, Fischer M, Howard M. Interleukin 4 is a growth factor for activated thymocytes: Possible role in T-cell ontogeny. Proc Natl Acad Sci USA 1987; 84:3856-3860.
Meilin A, Sharabi Y, Shoham J. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium V. Proliferation regulating activities in supernatants of human thymic epithelial cell cultures. Int J Immunopharmacol 1997; 19:39-47.
Barnes MJ, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity 2009; 31:401-411.
Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 2009; 30:636-645.
Mittal SK, Roche PA. Suppression of antigen presentation by IL-10. Curr Opin Immunol 2015; 34:22-27.
Patel DD, Whichard LP, Radcliff G, Denning SM, Haynes BF. Characterization of human thymic epithelial cell surface antigens: phenotypic similarity of thymic epithelial cells to epidermal keratinocytes. J Clin Immunol 1995; 15:80-92.