Impaired FcεRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of fyn deficiency in mast cells
Impaired FcεRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of fyn deficiency in mast cells
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DOI：
10.4049/jimmunol.175.11.7602
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Rivera, J
中科院分区：
文献类型：
--
作者：
Gomez, G;Gonzalez-Espinosa, C;Rivera, J
Fyn激酶是将Fc γ RI偶联至肥大细胞脱粒的关键贡献者。一个有限的宏阵列分析Fc β RI诱导的基因表达表明，在脂质代谢，类花生酸和谷胱甘肽代谢，细胞因子的产生潜在的缺陷。对这些反应的生化分析显示，Fyn缺陷型肥大细胞不能分泌炎性类花生酸产物白三烯B-4和C-4、细胞因子IL-6和TNF以及趋化因子CCL 2（MCP-1）和CCL 4（MIP-1 β）。FcCRRI诱导的花生四烯酸生成和细胞因子mRNA的正常诱导是有缺陷的。观察到JNK和p38 MAPK活化缺陷，而ERK 1/2和胞浆磷脂酶A（2）（S505）磷酸化正常。药理学研究表明JNK活性与花生四烯酸的产生有关。Fc β RI介导的I κ B激酶13和1 κ B α磷酸化和降解的活化是有缺陷的，导致驱动肥大细胞中IL-6和TNF产生的核NF-κ B DNA结合活性显著降低。然而，并非所有细胞因子都受到影响，因为IL-13的产生和分泌增加。这些研究揭示了Fyn激酶在多种肥大细胞炎症反应中的主要积极作用，并证明了某些细胞因子的选择性负调节作用。
Fyn kinase is a key contributor in coupling Fc epsilon RI to mast cell degranulation. A limited macroarray analysis of Fc epsilon RI-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 B-4 and C-4, the cytokines IL-6 and TNF, and chemokines CCL2 (MCP-1) and CCL4 (MIP-1 beta). Fc epsilon RI-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 A(2) (S505) phosphorylation was normal. Pharmacological studies revealed that JNK activity was associated with generation of arachidonic acid. Fc epsilon RI-mediated activation of I kappa B kinase 13 and 1 kappa B alpha phosphorylation and degradation was defective resulting in a marked decrease of the nuclear NF-kappa B 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.