Existence of autocrine loop between interleukin‐6 and tranforming growth factor‐β₁ in activated rat pancreatic stellate cells

Abstract

Interleukin (IL)-6 is a proinflammatory cytokine assumed to participate in pancreatic fibrosis by activating pancreatic stellate cells (PSCs). Autocrine TGF-beta1 is to central in PSC functional regulation. In this study, we examined IL-6 secretion from culture-activated rat PSCs and its regulatory mechanism. Activated PSCs express and secrete IL-6. When anti-TGF-beta1 neutralizing antibody was added in the culture medium, IL-6 secretion from activated PSCs was inhibited, whereas exogenous TGF-beta1 added in the culture medium enhanced IL-6 expression and secretion by PSCs in a dose dependent manner. Infection of PSCs with an adenovirus expressing dominant-negative Smad2/3 attenuated basal and TGF-beta1-stimulated IL-6 expression and secretion of PSCs. We also demonstrated the reciprocal effect of PSCs-secreted IL-6 on autocrine TGF-beta1. Anti-IL-6 neutralizing antibody inhibited TGF-beta1 secretion from PSCs. Preincubation of cells with 10 nM PD98059, an extracellular signal-regulated kinase (ERK)-dependent pathway inhibitor, attenuated IL-6-enhanced TGF-beta1 expression and secretion of PSCs. In addition, IL-6 activated ERK in PSCs. These data indicate the existence of autocrine loop between IL-6 and TGF-beta1 through ERK- and Smad2/3-dependent pathways in activated PSCs.

Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a TGF-β-dependent mechanism

“…8), suggesting a pivotal role of the TGF-␤1-Smad2 signaling pathway in SPC-induced SMC differentiation. Accumulating evidence demonstrates that expression of TGF-␤1 can be induced by various cytokines, including IL-1␤, IL-6, and IL-10 and angiotensin II (Aoki et al, 2006b;Aoki et al, 2006a;Sinuani et al, 2006;Wang et al, 2006), and that the IL-1␤- and IL-6-induced expression of TGF-␤1 is mediated by an ERK-dependent pathway (Aoki et al, 2006b;Aoki et al, 2006a). Moreover, angiotensin II induces the late activation of Smad2/3 by an ERK-dependent pathway, and angiotensin IIinduced secretion of TGF-␤1 is responsible for the activation of Smad2/3 in vascular SMCs (Wang et al, 2006).…”

Mathematical model of chronic pancreatitis

“…For simplicity, we assumed that the cytokines are produced (by PSCs or macrophages) at a constant rate, and they undergo a natural decay with constant rates (9,10,24,25,27). However, in the production of IL-6, we also included enhancement of IL-6 production by TGF-β (24).…”

“…During pancreatic inflammation, endothelial cells secrete monocyte chemoattractant protein (MCP-1) (14-19), triggering recruitment of monocytes from the blood into the inflamed area (20,21). Upon entering the pancreas, monocytes differentiate into macrophages, which secrete tumor necrosis factor alpha (TNF-α) (22,23) and interleukin 6 (IL-6) (24,25). TNF-α and IL-6 from macrophages, along with other soluble factors, are then capable of causing PSC activation.…”

Signal transduction in pancreatic stellate cells

“…It has been proposed that an autocrine loop exists between TGF-b1 and IL-1b through Smad3-and ERK-dependent pathways [74]. Another autocrine loop may exist between IL-6 and TGF-b1 through ERK-and Smad2/3-dependent pathways in activated PSCs [75]. Interestingly, it has been recently shown that cyclooxygenase-2 expression, induced by TGF-b1 through Smad2/ 3-dependent pathways, is required for activated PSCs to respond to proinflammatory cytokines [19].…”