Stress-dependent control of cytokine production in mast cells stimulated through FceRI and Toll-like 4 receptors

Abstract

Mast cells (MC) play an important role on allergic reactions triggered by the IgE/Antigen-dependent crosslinking of the high affinity IgE receptor (FceRI), and their participation on inflammatory innate immune responses triggered by Toll-like receptors (TLRs) has started to be documented. Physiological conditions such as stress exert a modulatory effect on allergic reactions since stress mediators activate signaling cascades that either interfere or potentiate the FceRI-dependent cytokine production. Recently, the effect of stress mediators on cytokine production induced after Toll-like receptors (TLRs) has started to be addressed in this cell type. In a recent paper, we analyzed the effects of stress induced by forced swimming (FS) on the MC-dependent production of Tumor Necrosis Factor (TNF) induced by a single intraperitoneal injection of bacterial lipopolysaccharide (LPS) in mice. FS provoked an immediate and transient inhibition of LPS-elicited TNF accumulation in peritoneum, which lasted around to 30 min. With the aim to identify the mediator of stress responsible for the inhibition, we first blocked catecholamine release from adrenal glands (by adrenalectomy) or nerve terminals (with DSP4 treatment). With these manipulations we observed an important increase on basal ip TNF levels and enhanced LPS-induced TNF release without any effect on stress-induced inhibitory effects. We then pre-treated animals with the glucocorticoid receptor antagonist mifepristone and did not observe any change on basal levels or stress-induced inhibition of TNF release. Finally, we administered an antagonist of acetylcholine receptors (mecamylamine) and observed an increase on basal levels of ip TNF values together with an important blockage of stress effects. Those results show for the first time that early MC-derived TNF secretion after Toll-like receptors is negatively controlled by adrenaline and transiently inhibited by the anti-inflammatory cholinergic reflex. Our results adds to the description of stress effects on MC activation and open new avenues in the research on the control of chronic inflammatory reactions associated with long term MC-dependent cytokine secretion.