MKK3 regulates mast cell IL-4 production through Egr1. (151.9)

Abstract

Abstract Mast cells play a central role in allergic inflammation and are activated through crosslinking of IgE receptors, initiating a signaling cascade resulting in production of biologically potent mediators. Signaling pathways in the regulation of specific mediators remain incompletely defined. Here, we examined the role of mitogen-activated protein kinase (MAPK) kinase 3 (MKK3) in IgE-dependent mast cell activation. In an in vivo model of passive cutaneous anaphylaxis, MKK3-deficient mice showed a deficit in late phase IgE-dependent inflammation. To characterize the mechanism of this deficiency, we cultured bone marrow-derived mast cells (BMMCs) from wild-type and MKK3 knockout (KO) mice. We found that IgE-mediated mast cell activation induced rapid MKK3 phosphorylation by 5 minutes, diminishing slowly after 6 hours. In MKK3-deficient BMMCs, phosphorylation of p38 was reduced at early and later time points. Among 40 cytokines tested using a protein array, IL-4 was the only cytokine specifically down-regulated in MKK3-deficient BMMCs. Furthermore, early growth response-1 (Egr1) bound to the promoter of IL-4 in FcϵRI-activated mast cells and Egr1 transcription factor activity was diminished from 1-6 hours in MKK3-deficient BMMCs. Thus, MKK3 is a specific regulator of IgE-induced IL-4 production likely through regulating Egr1 activity in mast cells.