Autocrine loop between TGF-β₁ and IL-1β through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells

Abstract

Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1beta has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1beta secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1beta mRNA and secrete IL-1beta peptide. Inhibition of TGF-beta(1) activity secreted from PSCs by TGF-beta(1)-neutralizing antibody attenuated IL-1beta secretion from PSCs. Exogenous TGF-beta(1) increased IL-1beta expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF-beta(1)-stimulated IL-1beta expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1beta activity secreted from PSCs by IL-1beta-neutralizing antibody attenuated TGF-beta(1) secretion from PSCs. Exogenous IL-1beta enhanced TGF-beta(1) expression and secretion by PSCs. IL-1beta activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1beta enhancement of TGF-beta(1) expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-beta(1) and IL-1beta in activated PSCs through Smad3- and ERK-dependent pathways.

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

“…Several studies have suggested that ERK is able to modulate IL-1␤ enhancement of TGF␤1 expression, since the MEK-1 inhibitor PD98059 can reverse the stimulation of TGF␤1 by IL-1␤ (37). In our studies, using the more specific MEK inhibitor U0126, no effect of ERK-1/2 phosphorylation blockade was observed on the levels of TGF␤RII mRNA or protein, which suggests that another pathway is involved.…”

Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

“…All these signalling molecules have previously been identified as key components of the intracellular network triggering PSC activation [14,15,25] . Furthermore, ET-1 significantly stimulated expression of two cytokines that have previously been suggested as autocrine enhancers of PSC activation, IL-1β and IL-6 [18,19] . Since both cytokines are well-established pro-inflammatory mediators, our data also implicate, for the first time, ET-1 in the enhancement of local inflammatory reactions in the pancreas.…”

Effect of the IkBα mutant gene delivery to mesenchymal stem cells on rat chronic pancreatitis

“…Following liver damage in CP, acinar, duct, endothelial, and inflammatory cells all release a large amount of inflammatory mediators, such as platelet-derived growth factor, transforming growth factor-beta (TGF-β), interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and so on, resulting in PSC activation, aggregation, and proliferation Aoki et al, 2006;Habisch et al, 2010). Finally, the cell morphology and function of PSCs are changed and self-activated to promote matrix proliferation (Apte et al, 1998Phillips et al, 2003).…”