Suppressors of Cytokine Signaling Inhibit Tubular Epithelial Cell-Myofibroblast Transdifferentiation

Abstract

Background/Aims: Tubular epithelial cell-myofibroblast transdifferentiation (TEMT) can be induced by diverse cytokines. The suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling. This study is aimed at examining the role of SOCS-1 and SOCS-3 in TEMT induced by cytokines. Methods: The cell ultrastructure was observed using transmission electron microscopy. The protein and mRNA levels of cytokeratin 18 (CK18) and α-smooth muscle actin (α-SMA) were detected by immunocytochemistry, Western blot and real-time PCR. The levels of phosphorylated-signal transducer and activator of transcription (p-STAT) 1 and 3 were detected by Western blot. The protein and mRNA levels of SOCS-1 and SOCS-3 were detected by Western blot and real-time PCR. The levels of collagen type I and fibronectin (FN) were determined by ELISA. Results: Interleukin-1β (IL-1β) and oncostatin M (OSM) were able to downregulate CK18 expression and upregulate α-SMA, p-STAT1, p-STAT3, collagen type I and FN expression in cultured human renal proximal tubular epithelial cells (HKCs), whereas pretreatment with AG490 prevented these expression changes from occurring. All of the changes induced by IL-1β or OSM could be decreased by SOCS-1 and SOCS-3 overexpression, and were increased by SOCS-1 and SOCS-3 knockdown. Conclusions: SOCS-1 and SOCS-3 can prevent tubulointerstitial fibrosis by inhibiting TEMT, which may be connected with the activation of STAT1 and STAT3.

IL-18 induces profibrotic renal tubular cell injury via STAT3 activation

“…STAT3 inhibition with S3I-201, however, dramatically reduced IL-18-induced ␣-SMA expression and collagen production in TECs, suggesting that STAT3 mediates IL-18-induced profibrotic renal tubular cell injury. These findings are corroborated by Liu et al (24), who demonstrated that IL-1␤ induces EMT in proximal tubular cells via the JAK/STAT signaling pathway.…”

“…SOCS proteins negatively regulate JAK/STAT signaling by either binding to and directly inhibiting JAK tyrosine kinase activity or competing with STATs for phosphotyrosine binding sites on cytokine receptors (21). While increased SOCS3 expression has been demonstrated in renal tubular cells in vitro in response to IL-1␤ stimulation (24), SOCS3 expression during renal obstruction and the effect of obstruction-induced IL-18 production on SOCS3 expression have not previously been evaluated. Our results demonstrate that renal cortical SOCS3 protein and mRNA expression peak in response to 1 wk of renal obstruction and remain significantly elevated in response to 2 wk of obstruction.…”

Relationships among injury, fibrosis, and time in human kidney transplants

“…It may be significant that OSMR, ITGB6, and MIR21 are among the top TxBx-corrected transcripts. OSM is expressed in several cell types and has been implicated in wound repair and atrophy fibrosis (63,64). Latent TGFB1 is activated in part by expression of ITGB6 on injured epithelium (58,65) and has many potential roles in repair, perhaps involving the MIR21 pathway (66).…”

SOCS-3 is downregulated in progressive CKD patients and regulates proliferation in human renal proximal tubule cells in a STAT1/3 independent manner

“…A study by Liu et al 43 has also investigated the role of SOCS-3 in a human proximal tubule cell line. In their experiments, OSM induced EMT and this was enhanced by SOCS-3 knockdown.…”

“…[40][41][42] In this study, we investigated whether SOCS-3 may also be an important regulator of STAT1/3 signaling in renal tubule cells in vitro and in vivo. So far, only one study has investigated the expression of SOCS-3 in one kidney cell line 43 but no study has been performed in human kidney biopsy material or using common cell lines, like HK-2 or LLC-PK1. In this study, we found that SOCS-3 is downregulated in patients with progressive decline of renal function.…”