Regulation of the Immune Response by Leptin
5. LEPTIN AND PATHOPHYSIOLOGY OF THE IMMUNE SYSTEM It seems to be generally accepted that leptin may be an important signal that connects
MAPK activation by leptin is necessary for the antiapoptotic effect in human mono- nuclear cells (25).
Evidence that leptin initiates a signaling cascade involving MAPK-dependent path- way has been also found in neutrophils (31), whereby leptin also inhibits apoptotic path- ways. Neutrophils seem to express only the short isoform of leptin receptor, Ob-Ra (32), which does not signal via the JAK–STAT pathway, but may be sufficient to stimulate the MAPK pathway.
We have also explored the PI3K pathway in peripheral blood mononuclear cells (PBMC) in response to human leptin. Thus, PI3K activity associated with tyrosine phosphorylated proteins is found to be increased more than threefold after 10 nM lep- tin stimulation (53). PI3K activation is regulated by the association of tyrosine phospho- rylated proteins with the SH2 domains of p85. Thus, in response to leptin, a band corresponding to the molecular mass of the insulin receptor substrate (IRS)-1 and sev- eral bands of 60 to 70 kDa (including Sam68) are phosphorylated and associated with p85 in a dose–response manner, similar to our previous data in response to insulin (53,60,71). Maximal response is observed at 10 nM leptin and 5 min incubation time.
The activation of PI3K in a macrophage cell line has also been demonstrated (65).
Leptin also initiates the activation of PI3K pathway in neutrophils, even though they express only the short isoform of leptin receptor (31). This signaling pathway is involved in transducing leptin-mediated antiapoptotic signals into neutrophils.
Finally, new mechanisms by which leptin can promote inflammatory responses have been recently provided, at least in alveolar macrophages—i.e., the upregulation of phospholipase A2 activity and phospholipase A2Lprotein levels (24).
5. LEPTIN AND PATHOPHYSIOLOGY OF THE IMMUNE SYSTEM
respond to leptin properly, central versus peripheral leptin resistance may underlie the pathophysiology of obesity, and therefore, the study of leptin signaling at central versus peripheral levels may improve our understanding of the mechanisms involved in the metabolic and immune alterations in the metabolic syndrome that lead to increased cardiovascular risk. These molecular defects may connect the thrifty phenotype with the proinflammatory phenotype in a common trait that turns out to be lethal in the Westernized way of life.
Recent data also suggest the possible role of leptin in the pathophysiology of some autoimmune diseases. This has already been demonstrated in some animal models, such as the experimental autoimmune encephalomyelitis, antigen-induced arthritis, models of type 1 diabetes, autoimmune colitis, and experimental hepatitis, as well as some clinical studies (15,17,72–74). However, this is the subject of other chapters in this book, and we are not reviewing the possible role of leptin in the pathophysiology of immune diseases.
Finally, leptin administration has been proposed as a possible treatment, not only for the immunodeficiency of obesity syndromes caused by a deficit of leptin (46), but also in some immunodeficiency syndromes, such as the common variable immunodeficiency, to improve both function of T-cells and the synthesis of immunoglobulins. In this line, recent data obtained using cells from patients in vitro support this hypothesis (75).
6. CONCLUSIONS
In conclusion, leptin may be considered as a therapeutic target in some clinical situations, such as proinflammatory states or autoimmune diseases, to control an excess of immune response, as well as in other clinical situations, such as starving, excess of exercise, or immune deficiencies, to improve the impaired immune response. That is why the investigation of the role of leptin in the regulation of the immune response is still a challenge for the future.
REFERENCES
1. Zhang Y, Proenca R, Maffei M, et al. Nature 1994;372:425–432.
2. Flier JS. Cell 1995;80:15–18.
3. Ahima RS, Prabakaran D, Mantzoros C, et al. Nature 1996;382:250–252.
4. Lord GM, Matarese G, Howard JK, et al. Nature 1998;394:897–901.
5. Fantuzzi G, Faggioni R. J Leukoc Biol 2000;68:437–446.
6. Howard JK, Lord GM, Matarese GJ. Clin Invest 1999;104:1041–1059.
7. Montez JM, Soukas A, Asilmaz E, et al. Proc Natl Acad Sci USA 2005;102:2537–2542.
8. Palacio A, Lopez M, Perez-Bravo F, et al. J Clin Endocrinol Metab 2002;87:3040–3046.
9. Bennet BD, Solar GP, Yuan JQ, et al. Curr Biol 1996;6:1170–1180.
10. Sánchez-Margalet V, Martín-Romero C, Santos-Alvarez J, et al. Clin Exp Immunol 2003;133:11–19.
11. Madej T, Boguski MS, Bryant SH. FEBS Lett 1995;373:13–18.
12. Tartaglia LA, Dembski M, Weng X, et al. Cell 1995;83:1263–1271.
13. Baumann H, Morella KK, White DW, et al. Proc Natl Acad Sci USA 1996;93:8374–8378.
14. Lord GM, Matarese G, Howard JK. Science 2001;292:855–856.
15. Matarese G. European Cytokine Network 2000;11:7–13.
16. Faggioni R, Feingold KR, Grunfeld C. FASEB J 2001;15:2565–2571.
17. Matarese G, Moschos S, Mantzoros CS. J Immunol 2005;173:3137–3142.
18. Loffreda S, Yang SQ, Lin HZ, et al. FASEB J 1998;12:57–65.
19. Lee FY, Li Y, Yang EK, et al. Am J Physiol 1999 ;276:C386–C394.
20. Sarraf P, Frederich RC, Turner EM, et al. J Exp Med 1997;185:171–175.
21. Santos-Alvarez J, Goberna R, Sánchez-Margalet V. Cell Immunol 1999;194:6–11.
22. Gabay C, Dreyer M, Pellegrinelli N, et al. J Clin Endocrinol Metab 2001;86:783–791.
23. Meier CA, Chicheportiche R, Dreyer M, et al. Cytokine 2003;21:43–47.
24. Mancuso P, Canetti C, Gottschalk A, et al. Am J Physiol Lung Cell Mol Physiol 2004;L287:497–502.
25. Najib S, Sanchez-Margalet V. Cell Immunol 2002;220:143–149.
26. Sánchez-Pozo C, Rodriguez-Bano J, Dominguez-Castellano A, et al. Clin Exp Immunol 2003;134:
464–469.
27. Maingrette F, Renier G. Diabetes 2003;52:2121–2128.
28. Curat CA, Miranville A, Sengenes C, et al. Diabetes 2004;53:1285–1292.
29. Mattioli B, Straface E, Quaranta MG, et al. J Immunol 2005;174:6820–6828.
30. Caldefie-Chezet F, Poulin A, Tridon A, et al. J Leukoc Biol 2001;69:414–418.
31. Bruno A, Conus S, Schmid I, et al. J Immunol 2005;174:8090–8096.
32. Zarkesh-Esfahani H, Pockley AG, Wu Z, et al. J Immunol 2004;172:1809–1814.
33. Caldefie-Chezet F, Poulin A, Vasson MP. Free Radic Res 2003;37:809–814.
34. Moore SI, Huffnagle GB, Chen GH, et al. Infect Immun 2003;71:4182–4185.
35. Tian Z, Sun R, Wei H, et al. Biochem Biophys Res Commun 2002;298(3):297–302.
36. Zhao Y, Sun R, You L, et al. Biochem Biophys Res Commun 2003;300:247–252.
37. La Cava A, Matarese G. Nat Rev Immunol 2004;4:371–379.
38. Li Z, Lin H, Yang S, et al. Gastroenterology 2002;123:1304–1310.
39. Guebre-Xabier M, Yang S, Lin HZ, et al. Hepatology 2000;31:633–640.
40. Mandel MA, Mahmoud AAF. J Immunol 1978;120:1375–1377.
41. Chandra RK, Au B. Int Arch Allergy Appl Immunol 1980;62:94–98.
42. Martín-Romero C, Santos-Alvarez J, Goberna R, et al. Cell Immunol 2000;199:15–24.
43. Sánchez-Margalet V, Martín-Romero C, González-Yanes C, et al. Clin Exp Immunol 2002;129:119–124.
44. Lord GM, Matarese G, Howard JK, et al. J Leukoc Biol 2002;72:330–338.
45. Fujita Y, Murakami M, Ogawa Y, et al. Clin Exp Immunol 2002;128:21–26.
46. Farooqi IS, Matarese G, Lord GM, et al. J Clin Invest 2002;110:1093–1103.
47. Myers MG Jr. Recent Prog Horm Res 2004;59:287–304.
48. Ahima RS, Osei SY. Physiol Behav 2004;81:223–241.
49. Kishimoto T, Taga T, Akira S. Cell 1994;76:253–262.
50. Darnell JE Jr. Science 1997;277:1630–1635.
51. Ghilardi N, Skoda RC. Mol Endocrinol 1997;11:393–399.
52. Bjørbaek C, Uotani S, da Silva B, et al. J Biol Chem 1997;272:32,686–32,695.
53. Martín-Romero C, Sánchez-Margalet V. Cell Immunol 2001;212:83–91.
54. Tartaglia LA. J Biol Chem 1997;272:6093–6096.
55. Schwartz MW, Seeley RJ, Campfield LA, et al. J Clin Invest 1996;98:1101–1106.
56. Vaisse C, Halaas JL, Horvath CM, et al. Nat Genet 1996;14:95–97.
57. Sánchez-Margalet V, Martin-Romero C. Cell Immunol 2001;211:30–36.
58. Ihle JN. Nature 1995;377:591–594.
59. Fusaki N, Iwamatsu A, Iwashima M, et al. J Biol Chem 1995;272:6214–6219.
60. Najib S, Martin-Romero C, Gonzalez-Yanes C, et al. Cell Mol Life Sci 2005;62:36–43.
61. Hartmann AM, Nayler O, Schwaiger FW, et al. Mol Biol Cell 1999;10:3909–3926.
62. Rosenblum CI, Tota M, Cully D, et al. 1996;137:5178–5181.
63. Wang Y, Kuropatwinski KK, White DW, et al. J Biol Chem 1997;272:16,216–16,223.
64. McCowen KC, Chow JC, Smith RJ. Endocrinology 1998;139:4442–4447.
65. O’Rourke L, Yeaman SJ, Shepherd PR. Diabetes 2001;50:955–961.
66. Bjørbaek C, Buchholz RM, Davis SM, et al. J Biol Chem 2001;276:4747–4755.
67. Takahashi Y, Okimura Y, Mizuno I, et al. J Biol Chem 1997;272:12,897–12,900.
68. Kellerer M, Koch M, Metzinger E, et al. Diabetologia 1997;40:1358–1362.
69. Harvey J, McKay NG, Walker KS, et al. J Biol Chem 2000;275:4660–4669.
70. Van den Brink GR, O’Toole T, Hardwick JC, et al. Mol Cell Biol Res Commun 2000;4:144–150.
71. Sánchez-Margalet V, Najib S. FEBS Lett 1999;455:307–310.
72. Matarese G, Alviggi C, Sanna V, et al. J Clin Endocrinol Metab 2000;85:2483–2487.
73. Matarese G, La Cava A, Sanna V, et al. Trends Immunol 2002;23:182–187.
74. Fantuzzi G, Sennello JA, Batra A, et al. Clin Exp Immunol 2005;142:31–38.
75. Goldberg AC, Eliaschewitz FG, Montor WR, et al. Clin Immunol 2005;114:147–153.