High-Dose Leptin Activates Human Leukocytes Via Receptor Expression on Monocytes

Abstract

Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the 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 monocytes, 12 ± 4% for neutrophils, and 5 ± 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-α and IL-6 mRNA and a dose-dependent production of TNF-α and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3–5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-α (5-fold), IL-6 (19-fold), and IFN-γ (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.

Severe pulmonary metastasis in obese and diabetic mice

“…[19][20][21] A deficiency of leptin is responsible for severe impairments of both innate and acquired immunity, including the differentiation and activation of NK cells. 22 During the early phase of metastasis, cancer cells are recognized and destroyed by the host's immune system, especially by NK cells.…”

Zinc supplementation to HIV-1-infected pregnant women: Effects on maternal anthropometry, viral load, and early mother-to-child transmission

“…Zinc repletion in previously deficient subjects appears to upregulate the production of Th1-systemic cellular host defense proinflammatory cytokines including tumor necrosis factor (TNF)-a (Beck et al, 1997). In addition, zinc supplementation seems to promote the secretion of leptin (Mantzoros et al, 1998) and in humans, it has been shown that leptin can increase TNF-a and IL-6 production by peripheral blood mononuclear cells and monocytes (Zarkesh-Esfahani et al, 2001). TNF-a exerts a strong inhibitory effect on myosin expression in muscle cells (Acharyya et al, 2004) and is implicated in the pathophysiology of anorexia; these two mechanisms could lead to wasting.…”

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

“…6 Leptin is now known to have potent immunomodulatory actions. 7 Interactions between leptin and its receptors on immune cells regulate immune cell functions, 8,9 including phagocytosis 10 and cytokine production. 11 Leptin deficiency also sensitizes T cells to corticosteroidinduced apoptosis, which promotes thymic atrophy in ob/ob mice.…”