Molecular markers of adipose tissue function during the febrile response

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Reciprocal effects of interleukin-4 and interferon-γ on immunoglobulin E-mediated mast cell degranulation: a role for nitric oxide but not peroxynitrite or cyclic guanosine monophosphate

We report that cultured rat peritoneal cells spontaneously synthesize nitric oxide and this is associated with active suppression of mast cell secretory function. Addition of interleukin-4 (IL-4) or the nitric oxide synthase inhibitor N-monomethyl-l-arginine to peritoneal cells inhibited nitric oxide synthesis and enhanced anti-IgE-mediated mast cell degranulation, measured as serotonin release. Interferon-γ (IFN-γ) completely overcame the enhancement of serotonin release and suppression of nitrite production induced by IL-4. Over several experiments, with or without IL-4 and/or IFN-γ, serotonin release correlated inversely with nitrite production. On a cell-for-cell basis, non-mast cells produced ≈30 times more nitrite than mast cells in peritoneal cell populations, with or without IFN-γ stimulation. The nitric oxide donor S-nitrosoglutathione inhibited anti-IgE-induced serotonin release from purified mast cells, whereas 8-bromo-cyclic GMP, the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, superoxide dismutase and the peroxynitrite scavenger uric acid, were without effect. We conclude that IL-4 and IFN-γ reciprocally regulate mast cell secretory responsiveness via control of nitric oxide synthesis by accessory cells; the nitric oxide effect on mast cells is direct but does not involve cyclic GMP or peroxynitrite

Interferon-γ regulates the interaction of RBL-2H3 cells with fibronectin through production of nitric oxide

Interferon-γ (IFN-γ) is an important regulatory cytokine in cell proliferation, differentiation, adhesion, mediator release, and gene induction. This diversity of effector roles is achieved by a variety of incompletely understood mechanisms. In the mast cell (MC), IFN-γ downregulates mediator synthesis and secretion. The present study demonstrates and characterizes for the first time IFN-γ inhibition of adhesion of the MC analogue RBL-2H3 to the extracellular matrix protein fibronectin (FN). Inhibition requires preincubation of the cells with IFN-γ for 20 hr, and is statistically significant at 100 U/ml IFN-γ. Flow cytometry indicates that cell surface expression of very late antigen-4 (VLA-4), VLA-5, and the vitronectin receptor (VNR) remain constant following IFN-γ treatment, indicating the inhibitory effect of IFN-γ on adhesion to FN is not achieved through a reduction in integrin receptors for FN. Fluorescent labelling with Texas red phalloidin demonstrated rearrangement of the actin cytoskeleton in response to IFN-γ was not significant. The tyrosine phosphatase inhibitor vanadate, and the nitric oxide (NO) synthase inhibitor L-NAME, reduced the IFN-γ effect on adhesion to FN by 62 and 70%, respectively, demonstrating that the IFN-γ effect is dependent upon the production of NO, potentially though a tyrosine phosphatase dependent mechanism. The NO donors sodium nitroprusside and S-nitrosoglutathione mimicked the effect of IFN-γ. Thus, following stimulation with IFN-γ, NO plays an autocrine role in the MC, and is able to modulate integrin function. This adds to the pathways NO is able to inhibit in the mast cell, shows that endogenous NO is able to inhibit these pathways, and suggests NO is impinging upon an element common to many signalling mechanisms in the MC