Leptin Regulation of Monocytes Macrophages

Beta Switch Program

The Beta Switch Program by Sue Heintze

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Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflamma-tory cytokines both in vivo and in vitro, whereas exogenous leptin upregulated both phagocytosis and the production of cytokines (18). Furthermore, phenotypic abnormalities in macrophages from leptin-deficient, obese mice have beeen found (19). More important, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production (16). More specifically, murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. In this context, leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation (20).

Human leptin was found to stimulate proliferation and activation of human circulating monocytes in vitro, promoting the expression of activation markers CD69, CD25, CD38, CD71, in addition to increasing the expression of monocytes surface markers, such as HLA-DR, CD11b and CD11c (21). In addition, leptin potentiates the stimulatory effect of LPS or phorbol myristate acetate on the proliferation and activation of human monocytes. Moreover, leptin dose-dependently stimulates the production of proinflammatory cytokines by monocytes, i.e., TNF-a and IL-6 (21). The presence of both isoforms of the leptin receptor was also assessed. Later, it was found that leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes (22) and upregulates IP-10 (interferon-y-inducible protein) in monocytc cells (23). In alveolar macrophages, leptin augments leukotriene synthesis (24).

A possible role of leptin as a trophic factor to prevent apoptosis has also been found in serum-depleted human monocytes (25), further supporting the role of leptin as a growth factor for the monocyte. Moreover, leptin regulates monocyte function, as assessed by in vitro experiments measuring free-radical production. Thus, leptin was shown to stimulate the oxidative burst in control monocytes (26), and binding of leptin at the macrophage cell surface increases lipoprotein lipase expression, through oxida-tive stress- and protein kinase C (PKC)-dependent pathways. In this line, leptin has been found to increase oxidative stress in macrophages (27). Finally, leptin can also increase

Fig. 1. Role of leptin activating immune-competent cells.


Fig. 1. Role of leptin activating immune-competent cells.

chemotaxis of blood monocytes and may mediate the inflammatory infiltrate (28). On the other hand, human leptin seems to downregulate oxidative burst in previously activated monocytes (26).

Dendritic cells belong to the same cell lineage as monocytes/machrophages and also present leptin receptor (OBRb) in the cell surface (29). Thus, leptin has been also found to increase the production of IL-8, IL-12, IL-6, and TNF-a, whereas it decreases MIP-1-a production by dendritic cells. Similarly to leptin's effect on monocytes, it may also increase the survival of dendritic cells, and increase the expression of surface molecules, such as CD1a, CD80, CD83, or CD86.

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