Leptin ve İmmün Sistem

SüleymanDemirel Üniversitesi TIP FAKÜLTESİ DERGİSİ: 2007 Haziran; 14(2) Leptin ve İmmün Sistem Demircan Özbalcı, Mehmet Şahin Süleyman Demirel Üniversitesi Tıp Fakültesi İç Hastalıkları Bilim Dalı Özet Leptin, hipotalamustaki reseptörüne bağlanıp, Interlökin-1 üzerinden yaptığı etkiyle insanlarda yemek yeme hissini azaltarak kilo alımını engelleyen, sitokinlere benzer yapıda bir hormondur. Kandaki düzeyi vücut yağ dokusu ile doğru orantılıdır. Son zamanlarda yapılan çalışmalarda leptinin organizmada birçok sistem üzerinde etkilerinin olduğu ortaya çıkarılmıştır. Leptin hematopoez, sitokin sentezi, anjiogenez ve hipotalamus-hipofiz-adrenal aksta görevlidir. Yeni yapılan çalışmalarda immun düzenleyici etkileri de ortaya çıkmıştır. Obezitede etkin olan mekanizmanın , sekonder leptin yetmezliği olduğu görüşü ağırlık kazanmaya başlamıştır. Bu derlemede immün sistem üzerine olan etkileri ve kısaca obesitedeki rolü tartışılmıştır. Anahtar kelimeler: leptin, immün sistem, sitokin, obezite Abstract Leptin and Immune System Leptin is a cytokine-like hormone that makes an effect on decreasing the appetite via on Interleukin-1 after it bounds to its receptor in hypothalamus. The level of the hormone is directly proportional with the body fat tissue. Recent studies showed that Leptin has effects on multiple systems of organisms. Leptin has effects on hematopoesis, synthesis of cytokines, angiogenesis and hypothalamus- pituitary-adrenal axis. Immune regulatory functions of leptin are found in recent studies. The mechanism responsible in obesity is thought to be secondary leptin deficiency. In this review, its effects on immune system and briefly its role in obesity is discussed. Key words: leptin, immune system, cytokine, obesity

Anahtar Kelimeler:

leptin, immün sistem, sitokin, obezite

PDF

___

Maffei M, Fei H, Lee GH ,Dani C, Leroy P, Zhang Y, et al. Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci USA 1995; 92: 695760.
Flier JS. The adipocyte: storage depot or node on the energy information superhighway?. Cell 1995; 80: 15- 8.
Tartaglia, LA, Demski M, Weng X, Deng NH, Culpepper J, Devos R, et al. Identification and expression of cloning of a leptin receptor OB-R. Cell 1995; 83: 1263-1271.
Lee GH, Proenza R, Montez JM, Carroll KM, Darvishzadch JG, Lee JL et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 39: 632-635.
Pelleymounter MA., Cullen MJ., Baker MB., Hecht R., Winters D., Boone T. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269, 540-543.
Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB and Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet induced resistance to leptin action. Nat. Med. 1995; 1: 1311- 1314
Maffuci M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight reduced subjects. Nat. Med. 1995; 1: 1115- 1161.
Faggioni R, Feingold KR, Grunfeld C. Leptin regulation of the immune response and the immunodefiency of malnutrion. FASEB 2001 Symposium Nutrients as regulators of the Immune System.
Siegrist-Kaiser CA, Pauli V, Juge-Aurby CE, Boss O, Pernin A, Chin WW, et al. Direct effects of leptin on brown and white adipose tissue. J Clin. Invest: 1997; 100: 2858-2864.
Chandra RK. Cell mediated immunity in genetically obese C57BL/6J ob/ob mice. Am. J. Clin. Nutr. 1980; 33: 13-16.
Spicer LJ, Francisco CC. The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function. Endocrinology 1997; 138: 3374- 3379.
Pralong FP, Roudit R, Waeber G, Castillo E, Mosimann F, Thorens B, et al. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology 1998; 139: 4264-4268.
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper C, Devos R et al. Identification and expression cloning of a leptin receptor. Cell 1995; 83: 126371.
Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 269:543-6
Siegmund B, Lehr HA, Fantuzzi G. Leptin: a pivotal mediator of intestinal inflammation in mice. Gastroenterology 2002; 122: 2011 25.
Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest 1999; 104: 10519.
Fujita Y, Murakami M, Ogawa Y, Masuzaki H, Tanaka M, Ozaki S et al. Leptin inhibits stress-induced apoptosis of T lymphocytes. Clin Exp Immunol 2002; 128:21- 6.
Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C et al. Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity. Role of tumor necrosis factor alpha and IL-18. Proc Natl Acad Sci USA 2000; 97: 236772.
Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol. 2000 Oct; 68(4): 437-46
Frederich RC, Lollmann B, Hamann A, Napolitano- Rosen A, Kahn BB, Lowell BB et al. Expression of Ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest 1995; 96: 165863.
Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA, Feingold KR, et al. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am. J. Physiol. 1999; 276: 136-142.
Gainsford T, Wilson TA, Metcalf D, Handman E, Mc Farlane C, Ng A et al. Leptin can induce proliferation, differantiation, and functional activation of hemopoetic cells. Proc Natl Acad Sci USA 1996; 93: 14564-8.
Loffreda S, Rai R, Yang SQ et al. Leptin regulates proinflammatory immune responses. FASEB J 1998; 12: 5765.
Vaisse C, Halaas JL, Horvath CM, Darnell JE, Stoffel M. and Friendman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 1996; 14: 95-97.
Kellerer M, Koch M, Metzinger E, Mushack J, Capp E, Haring HU. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 1997; 40: 135862.
Martín-Romero C, Santos-Alvarez J, Goberna R, Sánchez-Margalet V. Human leptin enhances activation and proliferation of human circulating T lymphocytes. Cell Immunol 2000; 199: 1524.
Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol 1999; 194: 6-11
Scheinbenbogen C, Keilholz U, Richter M, Andressen R, Hunstein W. The interleukin-2 receptor in human monocytes and macrophages: regulation of expression and release of the alpha and beta chains (p55 and p75). Res Immunol 1992; 143: 33-7.
Czerniecki BJ, Carter C, Rivoltini L, Koski GK, Kim HI, Weng DE et al. Calcium ionophore-treated peripheral blood monocytes and dendritic cells rapidly display characteristics of activated dendritic cells. J Immunol 1997; 159: 3823-37.
Darcissac EC, Bahr GM, Parant MA, Chedid LA, Riveau GJ. Selective induction of CD11a, b, c/CD18 and CD54 expression at the cell surface of human leucocytes by muramyl peptides. Cell Immunol 1996; 169: 294-301.
De Maria R, Cifone MG, Trotta R, Rippo MR, Festuccia C, SAntoni A et al.. Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. J Exp Med 1994; 180:19992004.
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998; 12: 57-65.
Lee FY, Li Y, Yang EK, Yang SQ, Lin HZ, Trush MA, et al. Phenotypic abnormalities in macrophages from leptin deficient, obese mice. Am. J. Physiol. 1999; 276: 386-394.
Zarkesh E, Pockley G, Metcalfe RA, Bidlingmaier M, Wu Z, Ajami A, et al. High-dose leptin activates human leucocytes via receptor expression on monocytes. J Immunol. 2001; 167: 4593-4599.
Gabay C, Smith MF, Eidlen D, Arend WP. Interleukin 1 receptor antagonist (IL-1Ra) is an acute phase protein. J. Clin. Invest. 1997; 99: 2930-2940.
Luheshi GN, Gardner JD, Rushford DA, Loudon AS, Rothwell NJ. Leptin actions on food intake and body temperature are mediated by IL-1. Proc Natl. Acad. Acad. Sxi. USA 1999; 96: 7047-7052.
Taub DD, Lloyd AR, Conlon K, Wang JM, Ortaldo JR, Harada A, et al. Recombinant human interferon- inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J. Ex. Med. 1993; 177: 1809-1814.
Juge-Aubry CE, Meier CA. Immunomodulatory action of leptin. Molecular and Cellular Endocrinology 2002; 194: 1-7.
Lord GM, Materese G, Howard JK, Bloom SR, Lechler RI. Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines. J Leukoc Biol 2002; 72: 330-8
Lord GM, Materese G, Howrad JK, Baker RJ, Bloom SR, and Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosupression. Nature (London) 1998; 394: 897- 901.
Meier CA, Bobbioni E, Gabey C, Assimacopoulos- jeannet F, Golay A, Dayer JM. Interleukin-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J. Clin. Endocrinol. Metab 2002; 87: 1184-1188.