Stem Cell Factor Augments FcεRI-Mediated TNF-α Production and Stimulates MAP Kinases via a Different Pathway in MC/9 Mast Cells

Abstract

AbstractMast cells express the receptor tyrosine kinase kit/stem cell factor receptor (SCFR) which is encoded by the proto-oncogene c-kit. Ligation of SCFR induces its dimerization and activation of its intrinsic tyrosine kinase activity leading to activation of Raf-1, phospholipases, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases. However, little is known about the downstream signals initiated by SCFR ligation except for activation of extracellular signal-regulated kinases. The murine mast cell line, MC/9, synthesizes and secretes TNF-α following the aggregation of high affinity Fc receptors for IgE (FcεRI). Ligation of SCFR or FcεRI on MC/9 cells resulted in the activation of all three MAP kinase family members, extracellular signal-regulated kinases, c-Jun amino-terminal kinase (JNK), and p38. Stem cell factor (SCF)-induced activation of JNK and p38 was insensitive to wortmannin, cyclosporin A, and FK506 whereas activation of these kinases through FcεRI was sensitive to these drugs. Coligation of SCFR augmented FcεRI-mediated activation of MAP kinases, especially JNK activation, and SCF augmented FcεRI-mediated TNF-α production in MC/9 cells, although SCF alone did not induce TNF-α production. This augmentation by SCF was regulated at the level of transcription, at least in part, since the promoter activity of TNF-α was enhanced following addition of SCF. These results demonstrate that SCF can augment FcεRI-mediated JNK activation and cytokine gene transcription but via pathways that are regulated differently than the ones activated through FcεRI.