Leptin potentiates IFN‐γ‐induced expression of nitric oxide synthase and cyclo‐oxygenase‐2 in murine macrophage J774A.1

Abstract

1 Leptin, a pleiotropic hormone believed to regulate body weight, has recently been associated with in¯ammatory states and immune activity. Here we have studied the e ect of leptin on expression of IFN-g-induced nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2), both prominent markers of macrophage activation, using the murine macrophage J774A.1 cell line.2 After 24 h of incubation, leptin (1 ± 10 mg ml 71 ) potently synergized with IFN-g (100 U ml 71 ) in nitric oxide (NO) release, evaluated as nitrite and nitrate (NO x ), and prostaglandin E 2 (PGE 2 ) production in culture medium. 3 The observed increase of NO and PGE 2 was related to enhanced expression of the respective inducible enzyme isoforms, measured in mRNA and protein by RT ± PCR and Western blot analysis, respectively. 4 When cells were stimulated only with leptin, a weak induction of NO and PGE 2 release and of the expression of related inducible enzymes was observed. 5 Moreover IFN-g increased the expression of the functional form of leptin receptor (Ob-Rb) and this e ect was potentiated by leptin in a concentration-dependent manner. 6 These data suggest that macrophages, among the peripheral immune cells, represent a target for leptin and con®rm the relevance of this hormone in the pathophysiology of in¯ammation.

Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation

“…A possible explanation is that in the early phase after peripheral nerve injury, the increase in COX-2 expression is noted in Schwann cells rather than in macrophages (25). Another is that COX-2 expression is increased by synergy with IFN-␥ treatment in the cell line (26). Further studies are needed to clarify the mechanism underlying the PSL-induced increase in COX-2 expression in the SCN.…”

Leptin Induces Macrophage Lipid Body Formation by a Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Mechanism

“…Recent studies have demonstrated a role for leptin in prostaglandin and leukotriene synthesis by leukocytes and suggest physiological activities for leptin in inflammation (9,46). Leukotriene synthesis is reduced in macrophages from leptin-deficient mice following bacterial infection (47).…”

“…Leukotriene synthesis is reduced in macrophages from leptin-deficient mice following bacterial infection (47). Moreover, leptin alone or in combination with other agonists increases prostaglandin and leukotriene production in macrophages (9,46). Mechanisms involved in leptin-induced priming for eicosanoid production are not fully defined and may involve different processes.…”

“…Mechanisms involved in leptin-induced priming for eicosanoid production are not fully defined and may involve different processes. Indeed, it has been demonstrated that leptin increases arachidonic acid availability, increases phospholipase A 2 protein expression and activity, and induces COX-2 expression (9,46,48). An additional mechanism that may contribute to the enhanced eicosanoid production is the compartmentalization of eicosanoid production at specialized sites, as in lipid bodies.…”

The Inflammatory Syndrome

“…However, obese individuals seem to be resistant to the hypothalamic effects of leptin (33); therefore, the catabolic pathways designed to reduce appetite and increase energy expenditure are not activated and excess body weight is maintained. Although many of leptin's effects result from a direct action of leptin on hypothalamic neurons, the functional leptin receptor (long-form or lep rb ) is also found on many tissues outside the central nervous system (CNS), including immune cells (35,36). Importantly, the mechanisms that are thought to contribute to hypothalamic leptin resistance (33), e.g., defective blood-brain barrier transport, are either moot or unproved in peripheral tissues, and no studies have documented peripheral leptin resistance in obese individuals.…”