Inhibition of Kit Expression by IL-4 and IL-10 in Murine Mast Cells: Role of STAT6 and Phosphatidylinositol 3′-Kinase

Abstract

The c-kit protooncogene encodes a receptor tyrosine kinase that is known to play a critical role in hemopoiesis and is essential for mast cell growth, differentiation, and cytokine production. Studies have shown that the Th2 cytokine IL-4 can down-regulate Kit expression on human and murine mast cells, but the mechanism of this down-regulation has remained unresolved. Using mouse bone marrow-derived mast cells, we demonstrate that IL-4-mediated Kit down-regulation requires STAT6 expression and phosphotidylinositide-3′-kinase activation. We also find that the Th2 cytokine IL-10 potently down-regulates Kit expression. IL-4 enhances IL-10-mediated inhibition in a manner that is STAT6 independent and phosphotidylinositide-3′-kinase dependent. Both IL-4- and IL-10-mediated Kit down-regulation were coupled with little or no change in c-kit mRNA levels, no significant change in Kit protein stability, but decreased total Kit protein expression. Inhibition of Kit expression by IL-4 and IL-10 resulted in a loss of Kit-mediated signaling, as evidenced by reduced IL-13 and TNF-α mRNA induction after stem cell factor stimulation. These data offer a role for STAT6 and phosphotidylinositide-3′-kinase in IL-4-mediated Kit down-regulation, coupled with the novel observation that IL-10 is a potent inhibitor of Kit expression and function. Regulating Kit expression and signaling may be essential to controlling mast cell-mediated inflammatory responses.

A Review on Maternal and Infant Microbiota and Their Implications for the Prevention and Treatment of Allergic Diseases

“…For the Treg cells that trigger immune tolerance, some intestinal helminths such as Strinoidogyne can induce Treg secretion in mice, and thus protect against colitis in a model of colitis [21], while disruption of the intestinal flora and antibiotic drugs reduce Treg cell differentiation in the intestine of mice [21]. Metabolites of commensal bacteria such as Bacteroides fragilis polysaccharides are also involved in the induction of Treg cell differentiation and promote the development of immune tolerance [22]. For Th17 cells, which are involved in immunity to exogenous pathogens, such as K. pneumoniae, S. aureus, S. enteritidis serum, and S. flexneri [14,23], their differentiation can be induced by segmented filamentous bacterium (SFB) [24].…”