Synergistic effect of pro-inflammatory TNFα and IL-17 in periostin mediated collagen deposition: Potential role in liver fibrosis

Abstract

Background The pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-17, have been implicated in the pathogenesis of liver fibrosis. In this study, we investigated the role of TNFα and IL-17 towards induction of profibrotic factor, periostin. Methods HepG2 cells were cultured and treated with inflammatory cytokines, TNFα and IL-17. Computational promoter sequence analysis of the periostin promoter was performed to define the putative binding sites for transcription factors. Transcription factors were analyzed by Western blot and Chromatin Immunoprecipitation. Periostin and transcription factor expression analysis was performed by RT-PCR, Western blot, and fluorescence microscopy. Type I collagen expression from fibroblast cultures was analyzed by Western blot and Sircol soluble collagen assay. Results Activation of HepG2 Cells with TNFα and IL-17 enhanced the expression of periostin (3.5 and 4.4 fold, respectively p<0.05) compared to untreated cells. However, combined treatment with both TNFα and IL-17 at similar concentration demonstrated a 13.3 fold increase in periostin (p<0.01), thus suggesting a synergistic role of these cytokines. Periostin promoter analysis and specific siRNA knock-down revealed that TNFα induces periostin through cJun, while IL-17 induced periostin via STAT-3 signaling mechanisms. Treatment of the supernatant from the cytokine activated HepG2 cells on fibroblast cultures induced enhanced expression of type I collagen (>9.1 fold, p<0.01), indicative of a direct fibrogenic effect of TNFα and IL-17. Conclusion TNFα and IL-17 induced fibrogenesis through cJun and STAT-3 mediated expression of profibrotic biomarker, periostin. Therefore, periostin might serve as a novel biomarker in early diagnosis of liver fibrosis.

Periostin on the road to nonalcoholic fatty liver disease

“…Other authors also reported higher serum periostin levels in patients with acute or chronic hepatitis compared with controls; in the same study, periostin levels were well associated with TGF-b1 and TGF-b2 [9]. Taken together, the aforementioned experimental and human data [7][8][9][10], periostin may mediate hepatic steatosis, inflammation, and fibrosis.…”

“…Importantly, in vitro activation of human hepatoblastoma cells (HepG2) with the proinflammatory and profibrogenic cytokines TNF-a, IL-17, or both, enhanced the expression of periostin by 3.5-, 4.4-, or 13.3-fold, respectively, compared to untreated cells [10]. It seems that periostin may mediate the type I collagen disposition induced by TNF-a and IL-6, thereby resulting in fibrosis [10].…”

“…It seems that periostin may mediate the type I collagen disposition induced by TNF-a and IL-6, thereby resulting in fibrosis [10].…”

Antifibrotic candidates of Selenium nanoparticles and selenium in the experimental model

“…Inflammation can also cause HSC activation and result in liver fibrosis. Products of the inflammatory cascade like: TNF-α, IL-6, IL-1β and COX-2 are elevated, independently of the etiology, in liver diseases (Amara et al, 2015).…”

“…Levels of circulating TNFα are increased in patients with liver fibrosis and are associated with poor prognosis (Amara et al, 2015). Thus, any approaches that attenuate its production, receptor activation, or downstream signal transduction should inhibit HSC activation and its subsidiary events (Wu and Zern, 2000).…”