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*
Division of Clinical Sciences (North), University of Sheffield, Sheffield, United Kingdom; and
Department of Medicine, Ludwig-Maximilians University, Munich, Germany
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-
and IL-6 mRNA and a
dose-dependent production of TNF- 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-
(5-fold), IL-6 (19-fold), and IFN-
(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.
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