Impaired FcepsilonRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn deficiency in mast cells.
Fyn kinase is a key contributor in coupling FcepsilonRI to mast cell degranulation. A limited macroarray analysis of FcepsilonRI-induced gene expression suggested potential defects in lipid metabolism, eicosanoid and glutathione metabolism, and cytokine production. Biochemical analysis of these responses revealed that Fyn-deficient mast cells failed to secrete the inflammatory eicosanoid products leukotrienes B4 and C4, the cytokines IL-6 and TNF, and chemokines CCL2 (MCP-1) and CCL4 (MIP-1beta). FcepsilonRI-induced generation of arachidonic acid and normal induction of cytokine mRNA were defective. Defects in JNK and p38 MAPK activation were observed, whereas ERK1/2 and cytosolic phospholipase A2 (S505) phosphorylation was normal. Pharmacological studies revealed that JNK activity was associated with generation of arachidonic acid. FcepsilonRI-mediated activation of IkappaB kinase beta and IkappaBalpha phosphorylation and degradation was defective resulting in a marked decrease of the nuclear NF-kappaB DNA binding activity that drives IL-6 and TNF production in mast cells. However, not all cytokine were affected, as IL-13 production and secretion was enhanced. These studies reveal a major positive role for Fyn kinase in multiple mast cell inflammatory responses and demonstrate a selective negative regulatory role for certain cytokines.
Gomez
Gregorio
G
Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Gonzalez-Espinosa
Claudia
C
Odom
Sandra
S
Baez
Gabriela
G
Cid
M Eugenia
ME
Ryan
John J
JJ
Rivera
Juan
J
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D015777:Eicosanoids / Q000096:biosynthesis* / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D020672:I-kappa B Proteins / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency* / Q000276:immunology; D017455:Receptors, IgE / Q000235:genetics* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D015777:Eicosanoids; D020672:I-kappa B Proteins; D018793:Interleukin-13; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D017455:Receptors, IgE; D000072000:NF-KappaB Inhibitor alpha; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4