Suppressors of cytokine signaling regulate Fc receptor signaling and cell activation during immune renal injury
Suppressors of cytokine signaling regulate Fc receptor signaling and cell activation during immune renal injury
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DOI：
10.4049/jimmunol.172.11.6969
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Egido, J
中科院分区：
文献类型：
--
作者：
Gómez-Guerrero, C;López-Franco, O;Egido, J
细胞因子信号转导抑制因子（SOCS）是酪氨酸诱导的蛋白质，其通过酪氨酸激酶途径调节受体信号转导。我们研究SOCS在肾脏疾病中的作用，分析SOCS是否调节IgG受体（Fc γ R）信号通路。在免疫复合物（IC）肾小球肾炎的实验模型中，SOCS家族基因（主要是SOCS-3）的肾脏表达显著增加，与蛋白尿和肾脏病变平行，并且蛋白质定位于肾小球和肾小管。在Fc γ R γ链缺陷的小鼠（γ（-/-）小鼠）中诱导肾炎导致SOCS-3和SOCS-1的肾脏表达降低。此外，在患有进行性肾炎的大鼠中，通过Fc片段给药阻断Fc γ R选择性抑制SOCS-3和SOCS-1，而不影响含丝氨酸诱导型Src同源性2的蛋白和SOCS-2。在培养的人肾小球系膜细胞（MC）和单核细胞，IC引起快速和短暂的诱导SOCS-3的表达。对于SOCS-1观察到类似的动力学，而SOCS-2表达非常低。来自γ（-/-）小鼠的MC未能对IC活化作出应答，证实了Fc γ R的参与。有趣的是，IC诱导SOCS-3和Tec酪氨酸激酶的酪氨酸磷酸化，并且这两种蛋白质在IC刺激的MC的裂解物中共沉淀，表明细胞内缔合。IC还激活了MC中的STAT通路，这被SOCS过表达所抑制，主要是SOCS-3。在SOCS-3敲低研究中，特异性反义寡核苷酸抑制系膜SOCS-3表达，导致IC诱导的STAT激活增加。我们的研究结果表明，SOCS可能在Fc γ R信号转导中发挥调节作用，并暗示SOCS是肾脏炎症过程中细胞活化的重要调节剂。
Suppressors of cytokine signaling (SOCS) are cytokine-inducible proteins that modulate receptor signaling via tyrosine kinase pathways. We investigate the role of SOCS in renal disease, analyzing whether SOCS regulate IgG receptor (FcgammaR) signal pathways. In experimental models of immune complex (IC) glomerulonephritis, the renal expression of SOCS family genes, mainly SOCS-3, significantly increased, in parallel with proteinuria and renal lesions, and the proteins were localized in glomeruli and tubulointerstitium. Induction of nephritis in mice with a deficiency in the FcgammaR gamma-chain (gamma(-/-) mice) resulted in a decrease in the renal expression of SOCS-3 and SOCS-1. Moreover, blockade of FcgammaR by Fc fragment administration in rats with ongoing nephritis selectively inhibited SOCS-3 and SOCS-1, without affecting cytokine-inducible Src homology 2-containing protein and SOCS-2. In cultured human mesangial cells (MC) and monocytes, IC caused a rapid and transient induction of SOCS-3 expression. Similar kinetics was observed for SOCS-1, whereas SOCS-2 expression was very low. MC from gamma(-/-) mice failed to respond to IC activation, confirming the participation of FcgammaR. Interestingly, IC induced tyrosine phosphorylation of SOCS-3 and Tec tyrosine kinase, and both proteins coprecipitated in Iysates from IC-stimulated MC, suggesting intracellular association. IC also activated STAT pathway in MC, which was suppressed by SOCS overexpression, mainly SOCS-3. In SOCS-3 knockdown studies, specific antisense oligonucleotides inhibited mesangial SOCS-3 expression, leading to an increase in the IC-induced STAT activation. Our results indicate that SOCS may play a regulatory role in FcgammaR signaling, and implicate SOCS as important modulators of cell activation during renal inflammation.