Interleukin-1 beta regulates proximal tubular cell transforming growth factor beta-1 signalling

Background. Increased transforming growth factor beta-1 (TGF beta) expression in the kidney is central not only to the pathogenesis of tubulointerstitial fibrosis but also in repair following acute injury. Recent work suggests that pro-inflammatory cytokines may determine epithelial cell responses to TGF beta in the contexts of acute injury and chronic wounding. Methods. In this study, we examined the effects of interleukin-1 beta (IL-1) on proximal tubular cell (PTC) response to TGF beta. Results. IL-1 induced the rapid activation of NF-κB in PTC. This was associated with inhibition of Smad2 and Smad3 signalling. NF-κB activation by IL-1 was transient, with a change from p65/p50 heterodimer to p50/p50 homodimer formation by 24 h and a switch to enhanced Smad signalling response to TGF beta. This was associated with IL-6 generation and prevented by IL-6 receptor blockade. Conclusion. In summary, IL-1 has a biphasic effect on PTC TGF beta signalling, with early NF-κB-mediated inhibition and delayed sensitization via an autocrine IL-6 loop. These results provide mechanistic insight into how acute and chronic inflammation help define epithelial cell response to TGF beta, and hence how TGF beta can have apparently contradictory roles, being involved in controlled healing following acute injury on one hand, yet the principal promoter of scarring in chronic disease on the other.