Stem cell factor induces AP-1-dependent mast cell IL-6 production via MAPK kinase 3 activity.
Mast cells are critical immune effectors abundant in tissues interfacing with the environment and have major roles in allergen-induced inflammation and host responses to infection. SCF is a regulator of mast cell function and growth. However, the critical mechanisms in SCF-directed events remain incompletely defined. Here, we have investigated the role of MKK3 in mast cell SCF signaling-dependent functions by using BMMCs from MKK3-deficient mice. MKK3 was phosphorylated rapidly and persistently following SCF-induced activation and contributed to mast cell proliferation but not survival or migration in response to SCF. Analysis of SCF-induced mast cell mediator secretion demonstrated that IL-6 production is specifically dependent on MKK3 signals, both independently and in concert with IgE. Analysis of SCF-induced signaling showed that sustained p38 phosphorylation was impaired in MKK3-deficient mast cells, where as early JNK and IκBα activation were enhanced. Notably, SCF-inducible expression and activation of c-Jun, a component of the AP-1 transcription factor, was significantly dependent on MKK3. Accordingly, AP-1 DNA-binding activity and interaction with the IL6 gene promoter was markedly impaired in MKK3-deficient mast cells, whereas transcription factors of the Egr family, NF-κB, and NFAT retained near-full activity. These results designate MKK3 as a novel, positive regulator of SCF-induced mast cell proliferation and a critical signaling protein for AP-1-dependent IL-6 production.
Departments of Microbiology & Immunology and Pediatrics, Dalhousie University, and Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Adam J
AJ
MacNeil
Departments of Microbiology & Immunology and Pediatrics, Dalhousie University, and Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Robert D
RD
Junkins
Departments of Microbiology & Immunology and Pediatrics, Dalhousie University, and Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Zhengli
Z
Wu
Departments of Microbiology & Immunology and Pediatrics, Dalhousie University, and Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada tong-jun.lin@dal.ca.
Tong-Jun
TJ
Lin
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D020672:I-kappa B Proteins / Q000378:metabolism; D007073:Immunoglobulin E / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000502:physiology*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D019089:Stem Cell Factor / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D015850:Interleukin-6; D019089:Stem Cell Factor; D018808:Transcription Factor AP-1; C577686:interleukin-6, mouse; D007073:Immunoglobulin E; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse
Jun transcription factor; ckit; protein kinases