Suppressors of cytokine signaling regulate Fc receptor signaling and cell activation during immune renal injury.
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 lysates 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.
Gómez-Guerrero
Carmen
C
Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Autónoma University, Madrid, Spain. cgomez@fjd.es
López-Franco
Oscar
O
Sanjuán
Guillermo
G
Hernández-Vargas
Purificación
P
Suzuki
Yusuke
Y
Ortiz-Muñoz
Guadalupe
G
Blanco
Julia
J
Egido
Jesús
J
D000818:Animals; D000936:Antigen-Antibody Complex / Q000633:toxicity; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011961:Receptors, Fc / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D000936:Antigen-Antibody Complex; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011961:Receptors, Fc; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C491589:Socs1 protein, rat; C491408:Socs2 protein, rat; C491410:Socs3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases