The Early Growth Response Factor-1 Is Involved in Stem Cell Factor (SCF)-induced Interleukin 13 Production by Mast Cells, but Is Dispensable for SCF-dependent Mast Cell Growth

Jason Berman,Tong-Jun Lin,Bo Li,Jin-Tian Tang

doi:10.1074/jbc.m610859200

Abstract

The stem cell factor (SCF) plays a central role in the regulation of mast cell function and growth. However, roles of transcription factors involved in these processes remain incompletely defined. The early growth response factor-1 (Egr-1) is a member of the zinc finger transcription factor family. A role for Egr-1 in SCF-induced mast cell activation and growth was investigated in mouse bone marrow-derived mast cells (BMMC). The stimulation of BMMC with SCF induced a strong expression of Egr-1 mRNA. SCF-induced Egr-1 nuclear translocation and DNA binding were demonstrated by electrophoretic mobility shift assay (EMSA) and immunofluorescence assay. SCF-induced IL-13 expression was significantly reduced at both mRNA and protein levels in Egr-1-deficient BMMC. In addition, the synergy between IgE and SCF on IL-13 and IL-4 production was reduced in Egr-1-deficient mast cells. Interestingly, Egr-1 deficiency had little effect on SCF-induced mast cell growth. SCF-induced Egr activation likely requires tyrosine phosphorylation because a tyrosine kinase inhibitor PP2 blocked SCF-induced nuclear protein binding to Egr probe as determined by EMSA. Thus, Egr-1 is required for SCF-induced IL-13 expression, but not mast cell growth. Egr-1 represents a novel mechanism for SCF-induced mast cell activation.

Highlights

Upon activation, mast cells secrete three major categories of mediators including preformed mediators such as histamine, lipid mediators such as leukotrienes and various cytokines and chemokines, such as IL-13 [1, 9]
stem cell factor (SCF) is a critical factor for both mast cell growth and functional activation [2]
SCF is critical for mast cell functional activation

Summary

Introduction

Mast cells secrete three major categories of mediators including preformed mediators such as histamine, lipid mediators such as leukotrienes and various cytokines and chemokines, such as IL-13 [1, 9]. We demonstrated that a transcription factor, early growth response-1 (Egr-1) is required for the Fc⑀RI-induced cytokine TNF and IL-13 production by mast cells [12]. It is unclear whether Egr-1 regulates SCF-induced mast cell cytokine production or SCF-dependent mast cell growth. Members of the Egr family have been associated in a large number of biological effects including cell growth and gene expression [13, 14]. We examined SCF-induced expression and function of Egr-1 in mast cells. By using Egr-1-deficient mast cells, we showed that SCF-induced IL-13 production requires Egr-1. Egr-1 represents a novel mechanism in SCF-induced cytokine IL-13 production by mast cells

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Conclusion