Die Stellung von Leptin im Immunsystem - Verbindung von Endokrinologie und Immunologie

Zusammenfassung

Leptin wurde primär als Hormon beschrieben, welches eine kritische Funktion in der Regulation der Nahrungsaufnahme sowie Adaption an Nahrungszustände, wie beispielsweise Fasten einnimmt. In der vorliegenden Übersichtsarbeit soll auf eine neue Rolle von Leptin eingegangen werden: die Position von Leptin im Immunsystem. Es werden hierbei die strukturellen Besonderheiten von Leptin beschrieben, die bereits auf eine Mediatorfunktion im Immunsystem hindeuten, sowie auf die Leptin-abhängigen Veränderungen einzelner Zellpopulationen des Immunsystems. Unterstützt werden diese in vitro-Daten durch in vivo-Untersuchungen in verschiedenen Tiermodellen sowie deskriptiven und funktionellen Daten von Leptin-defizienten Menschen, die ausführlich dargelegt sind. Leptin in seiner chimären Funktion als Hormon und Zytokin/Adipokin stellt somit exemplarisch eine Verbindung zwischen der Immunologie und Endokrinologie dar, welche neue pathophysiologische Zusammenhänge und damit therapeutische Optionen eröffnet.

Summary

Leptin is primarily known as a hormone regulating food intake and the adjustment to a distinct state of nutrition. In the present work a new function of leptin will be described, namely the role of leptin in the immune system. Structural characteristics of leptin and the leptin receptor already suggest an immune modulatory function. The effect of leptin on the various populations of immune cells in vitro will be described. These data are supported by findings obtained in in vivo animal models as well as descriptive and functional data from leptin-deficient humans which will be outlined in detail. In conclusion, the chimeric function of leptin as hormone and a cytokine/adipokine represents a unique link between the immune and the endocrine system thus opening a new field of research and therapeutic options.

Literatur

• 1 Ahima R S, Prabakaran D, Mantzoros C. et al . Role of leptin in the neuroendocrine response to fasting.  Nature. 1996;  382 250-252
• 2 Banks A S, Davis S M, Bates S H, Myers M G. Activation of downstream signals by the long form of the leptin receptor.  J Biol Chem. 2000;  275 14 563-14 572
• 3 Bernotiene E, Palmer G, Talabot-Ayer D, Szalay-Quinodoz I, Aubert M L, Gabay C. Delayed resolution of acute inflammation during zymosan-induced arthritis in leptin-deficient mice.  Arthritis Res Ther. 2004;  6 R256-263
• 4 Busso N, So A, Chobaz-Peclat V. et al . Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis.  J Immunol. 2002;  168 875-882
• 5 Coleman D L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.  Diabetologia. 1978;  14 141-148
• 6 Devos R, Guisez Y, Van der Heyden J. et al . Ligand-independent dimerization of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding.  J Biol Chem. 1997;  272 18 304-18 310
• 7 Dixit V D, Mielenz M, Taub D D, Parvizi N. Leptin induces growth hormone secretion from peripheral blood mononuclear cells via a protein kinase C- and nitric oxide-dependent mechanism.  Endocrinology. 2003;  144 5595-603
• 8 Faggioni R, Jones-Carson J, Reed D A. 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 U S A. 2000;  97 2367-2372
• 9 Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis.  J Leukoc Biol. 2000;  68 437-446
• 10 Farooqi I S, Matarese G, Lord G M. et al . Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.  J Clin Invest. 2002;  110 1093-1103
• 11 Fong T M, Huang R R, Tota M R. et al . Localization of leptin binding domain in the leptin receptor.  Mol Pharmacol. 1998;  53 234-240
• 12 Gainsford T, Willson T A, Metcalf D. et al . Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells.  Proc Natl Acad Sci U S A. 1996;  93 14 564-14 568
• 13 Hardwick J CH, Van den Brink G R, Offerhaus G J, Van Deventer S JH, Peppelenbosch M P. Leptin is a growth factor for colonic epithelial cells.  Gastroenterology. 2001;  121 79-90
• 14 Hileman S M, Tornoe J, Flier J S, Bjorbaek C. Transcellular transport of leptin by the short leptin receptor isoform ObRa in Madin-Darby Canine Kidney cells.  Endocrinology. 2000;  141 1955-1961
• 15 Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor.  J Biol Chem. 2001;  276 6343-6349
• 16 La Cava A, Matarese G. The weight of leptin in immunity.  Nat Rev Immunol. 2004;  4 371-379
• 17 Lord G M, Matarese G, Howard J K, Baker R J, Bloom S R, Lechler R I. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.  Nature. 1998;  394 897-901
• 18 Lord G M, Matarese G, Howard J K, Bloom S R, Lechler R I. Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines.  J Leukoc Biol. 2002;  72 330-338
• 19 Mancuso P, Gottschalk A, Phare S M, Peters-Golden M, Lukacs N W, Huffnagle G B. Leptin-deficient mice exhibit impaired host defense in gram-negative pneumonia.  J Immunol. 2002;  168 4018-4024
• 20 Mandel M A, Mahmoud A A. Impairment of cell-mediated immunity in mutation diabetic mice (db/db).  J Immunol. 1978;  120 1375-1377
• 21 Matarese G, Di Giacomo A, Sanna V. et al . Requirement for leptin in the induction and progression of autoimmune encephalomyelitis.  J Immunol. 2001;  166 5909-5916
• 22 Matarese G, Sanna V, Di Giacomo A. et al . Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males.  Eur J Immunol. 2001;  31 1324-1332
• 23 Montague C T, Farooqi I S, Whitehead J P. et al . Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 1997;  387 903-908
• 24 Mykoniatis A, Anton P M, Wlk M. et al . Leptin mediates Clostridium difficile toxin A-induced enteritis in mice.  Gastroenterology. 2003;  124 683-691
• 25 Ozata M, Ozdemir I C, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects.  J Clin Endocrinol Metab. 1999;  84 3686-3695
• 26 Palacio A, Lopez M, Perez-Bravo F. et al . Leptin levels are associated with immune response in malnourished infants.  J Clin Endocrinol Metab. 2002;  87 3040-3046
• 27 Sanchez-Margalet V, Martin-Romero C. Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway.  Cell Immunol. 2001;  211 30-36
• 28 Sanna V, Di Giacomo A, La Cava A. et al . Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses.  J Clin Invest. 2003;  111 241-250
• 29 Siegmund B, Lear-Kaul K C, Faggioni R, Fantuzzi G. Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis.  Eur J Immunol. 2002;  32 552-560
• 30 Siegmund B, Lehr H A, Fantuzzi G. Leptin: a pivotal mediator of intestinal inflammation in mice.  Gastroenterology. 2002;  122 2011-2025
• 31 Siegmund B, Sennello J A, Jones-Carson J. et al . Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice.  Gut. 2004;  53 965-972
• 32 Strobel A, Issad T, Camoin L. et al . A leptin missense mutation associated with hypogonadism and morbid obesity.  Nat Genet. 1998;  18 213-215
• 33 Tartaglia L A, Dembski M, Weng X. et al . Identification and expression cloning of a leptin receptor, OB-R.  Cell. 1995;  83 1263-1271
• 34 Tartaglia L A. The leptin receptor.  J Biol Chem. 1997;  272 6093-6096
• 35 Tarzi R M, Cook H T, Jackson I, Pusey C D, Lord G M. Leptin-deficient mice are protected from accelerated nephrotoxic nephritis.  Am J Pathol. 2004;  164 385-390
• 36 Yang S Q, Lin H Z, Lane M D, Clemens M, Diehl A M. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis.  Proc Natl Acad Sci U S A. 1997;  94 2557-2562
• 37 Zabeau L, Lavens D, Peelman F, Eyckerman S, Vandekerckhove J, Tavernier J. The ins and outs of leptin receptor activation.  FEBS Lett. 2003;  546 45-50
• 38 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432