High-dose leptin activates human leukocytes via receptor expression on monocytes

Leptin is capable of modulating the immune response. Proinflammatory cytoki nes induce leptin production, and we now demonstrate that leptin can direct ly activate the inflammatory response. RNA expression for the leptin recept or (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at th e protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 +/- 5% for m onocytes, 12 +/- 4% for neutrophils, and 5 +/- 1% for lymphocytes (only B l ymphocytes). Incubation of resting PBMCs with leptin induced rapid expressi on of TNF-alpha and IL-6 mRNA and a dose-dependent production of TNF-alpha and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (2 50 ng/ml, 3-5 days) Induced proliferation of resting cultured PBMCs and the ir secretion of TNF-alpha (5-fold), IL-6 (19-fold), and IFN-gamma (2.5-fold ), but had no effect on IL-4 secretion. The effect of leptin was distinct f rom, and additive to, that seen after exposure to endotoxin or activation b y the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin i nduces proinflammatory cytokine production by resting human PBMCs and augme nts the release of these cytokines from activated PBMCs in a pattern compat ible with the induction of Th1 cytokines. These results demonstrate that le ptin has a direct effect on the generation of an inflammatory response. Thi s is of relevance when considering leptin therapy and may partly explain th e relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.