Stem cell factor augments Fc epsilon RI-mediated TNF-alpha production and stimulates MAP kinases via a different pathway in MC/9 mast cells.
Mast 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-alpha following the aggregation of high affinity Fc receptors for IgE (Fc epsilonRI). Ligation of SCFR or Fc epsilonRI 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 Fc epsilonRI was sensitive to these drugs. Coligation of SCFR augmented Fc epsilonRI-mediated activation of MAP kinases, especially JNK activation, and SCF augmented Fc epsilonRI-mediated TNF-alpha production in MC/9 cells, although SCF alone did not induce TNF-alpha production. This augmentation by SCF was regulated at the level of transcription, at least in part, since the promoter activity of TNF-alpha was enhanced following addition of SCF. These results demonstrate that SCF can augment Fc epsilonRI-mediated JNK activation and cytokine gene transcription but via pathways that are regulated differently than the ones activated through Fc epsilonRI.
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
T
T
Ishizuka
H
H
Kawasome
N
N
Terada
K
K
Takeda
P
P
Gerwins
G M
GM
Keller
G L
GL
Johnson
E W
EW
Gelfand
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000595:Amino Acid Sequence; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000941:Antigens / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017455:Receptors, IgE / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus; D019089:Stem Cell Factor / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D000730:Androstadienes; D000941:Antigens; D011090:Polyenes; D011518:Proto-Oncogene Proteins; D017455:Receptors, IgE; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D010047:Ovalbumin; D019009:Proto-Oncogene Proteins c-kit; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus; D016559:Tacrolimus; D000077191:Wortmannin