IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway

Abstract

Excessive accumulation of collagen contributes to the fibrotic process. Several experimental studies have shown that IFN-gamma is effective in preventing fibrogenesis. IL-18, originally identified as an IFN-gamma-inducing factor, is a key mediator of inflammation and host defense responses. In this study, we investigated the regulatory effect of IL-18 on the expression of type I and III collagen genes in dermal fibroblasts. The exposure of human dermal fibroblasts (HDFs) to IL-18 resulted in a reduction of collagen gene expression and production. Also, IL-18 inhibited the fibrogenic cytokine transforming growth factor (TGF)-beta-induced collagen gene expression. Next, to determine the molecular mechanism involved in this regulation, we showed that IL-18-regulated collagen expression was blocked by small interfering RNA (siRNA)-mediated Ets-1 knockdown. Furthermore, we showed that IL-18 induced phosphorylation of extracellular signal-regulated kinase (ERK) within 10 minutes and that the ERK inhibitor PD98059 blocked the inhibitory effect of IL-18. IL-18 also inhibited the production of collagen in systemic sclerosis (SSc) dermal fibroblasts. Our data indicate that IL-18 downregulates collagen production in HDF directly via Ets-1 and the ERK pathway, suggesting that IL-18 may exert antifibrotic activities in dermal fibroblasts.

Interleukin 18 augments growth ability via NF-κB and p38/ATF2 pathways by targeting cyclin B1, cyclin B2, cyclin A2, and Bcl-2 in BRL-3A rat liver cells

“…It has been reported that IL-18 can be produced by multiple cell types, such as dendritic cells, keratinocytes, intestinal epithelial cells, Kupffer cells, activated monocytes/macrophages, adrenal cortex cells, articular chondrocytes, osteoblast and synovioblast (Okamura et al, 1995b;Kim et al, 2009;Sekiyama et al, 2006). Additionally, IL-18 is a pleiotropic factor and has various biological roles beyond that of inducing IFNγ, such as enhancing natural killer cell cytotoxicity, up-regulating intercellular adhesion molecules, and augmenting the production of GM-CSF, and stimulating the proliferation of activated T cells and the differentiation of T helper type 1 cells (Okamura et al, 1995b;Ushio et al, 1996;Raué et al, 2013).…”

Interleukin-18: Friend or Foe for Systemic Sclerosis?

“…In this article, Kim et al (2010) reported that IL-18 downregulates collagen production in human dermal fibroblasts directly via the E26 transformationspecific-1 and the ERK pathway, suggesting that IL-18 may exert antifibrotic activities in dermal fibroblasts from patients with systemic sclerosis (SSc). On the basis of these results, the authors concluded that IL-18 may represent a class of modulators with potential usefulness in treating excessive fibrosis in skin.…”

“…In fact, Kim et al (2010) discussed in their article that IL-18 has multiple functions and that it participates in both Th1-and Th2-mediated responses. Working in different systems, Zhang et al (2007) have reported that hepatic fibrosis is exacerbated by IL-18, which activates CD4 þ T cells, and that this effect is blocked by anti-IL-18 treatment Reddy et al (2008).…”

Schistosoma japonicum scFv-IL18 fusion DNA ameliorates hepatic fibrosis in schistosomiasis-infected mice via improving local concentration of IL-18 in liver

“…More strikingly, their results showed that IL-18 regulates Th1 and Th2 cytokines responses and reverses hepatic fibrosis. In addition, it has been reported that IL-18 exerted antifibrotic activities via downregulating collagen production in dermal fibroblasts (Kim et al, 2010). Wei et al (2009) noticed that IL-18 increases the Th1 type immune response in S. japonicum-infected mice with remarkable production of IFN-c and lower levels of IL-4 as compared to the control group.…”

“…The best explanation is that the specific SjscFv, which mainly located on egg embryo, vitellaria of female adult worm, ovary, eggs in uterus and intima of gut wall near reproductive system (Gao, 2010), are targeting the IL-18 to the site where parasitic eggs are embedded in the liver tissue. Then the site-specific accumulations of functional IL-18 will obviously downregulate the production of collagen as described elsewhere (Kim et al, 2010;Zhang et al, 2001).…”