Synergy between CD40 Ligation and IL-4 on fibroblast proliferation involves IL-4 receptor signaling
Synergy between CD40 Ligation and IL-4 on fibroblast proliferation involves IL-4 receptor signaling
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DOI：
10.4049/jimmunol.168.3.1139
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发表时间：
2002-02-01
影响因子：
4.4
通讯作者：
White, B
中科院分区：
文献类型：
--
作者：
Atamas, SP;Luzina, IG;White, B
纤维化可能是活化的细胞免疫应答的不期望的结果。这项工作的目的是确定CD 40连接和促纤维化细胞因子IL-4是否在调节成纤维细胞增殖和胶原蛋白产生中相互作用，如果是，则使用的机制。本研究发现，IL-4和在成纤维细胞表面连接CD 40的组合在刺激成纤维细胞增殖方面具有协同效应。相反，CD 40连接否定了IFN-γ对成纤维细胞增殖的抑制作用。成纤维细胞粗裂解物的蛋白质印迹分析显示，CD 40连接和IL-4之间的协同作用的潜在机制是在130 kDa的蛋白质的磷酸化，并在较小程度上，在95，85，和75 kDa。免疫沉淀-Western印迹实验表明，IL-4 R α，Janus激酶1，胰岛素受体底物1和胰岛素受体底物2的磷酸化水平，分子量接近观察到的130 kDa主要磷酸化条带的因子，响应于CD 40连接和IL-4的联合作用而增加。相反，没有证据表明协同作用是由IL-4 R α链、CD 40或自分泌促纤维化细胞因子IL-6和TGF-β的表达增加介导的。这些发现表明，成纤维细胞和分泌IL-4的细胞之间的CD 40-CD 40配体接触可能通过影响信号转导和降低IFN-γ的抗纤维化作用来促进IL-4的促纤维化作用。
Fibrosis can be an undesired consequence of activated cellular immune responses. The purpose of this work was to determine whether CD40 ligation and the pro-fibrotic cytokine IL-4 interact in regulating fibroblast proliferation and collagen production, and, if so, the mechanisms used. This study found that the combination of IL-4 and ligation of CD40 on the fibroblast cell surface had synergistic effects in stimulating fibroblast proliferation. In contrast, CD40 ligation negated the inhibitory effects of IFN-gamma on fibroblast proliferation. Western blotting analyses of fibroblast crude lysates revealed that a potential mechanism of the synergy between CD40 ligation and IL-4 was the phosphorylation of proteins at 130 kDa and, to a lesser degree, at 95, 85, and 75 kDa. Immunoprecipitation-Western blotting experiments showed that phosphorylation levels of IL-4Ralpha, Janus kinase 1, insulin receptor substrate 1, and insulin receptor substrate 2, factors with molecular mass close to the observed 130 kDa major phosphorylation band, increased in response to the combined CD40 ligation and IL-4 action. In contrast, there was no evidence that synergy was mediated by an increased expression of IL-4Ralpha chain, CD40, or the autocrine profibrotic cytokines IL-6 and TGF-beta. These findings suggest that CD40-CD40 ligand contacts between fibroblasts and cells secreting IL-4 may promote the profibrotic effects of IL-4 by affecting signal transduction and reducing the anti-fibrotic effects of IFN-gamma.