IL-10 receptor and coreceptor expression in quiescent and activated hepatic stellate cells

Abstract

Interleukin (IL)-10 expression is induced in activated hepatic stellate cells (HSC) in vitro and in vivo. We analyzed expression of IL-10 receptor (IL-10R) and coreceptor cytokine receptor family (CRF2–4) in HSC. We aimed to clone and sequence partial cDNA for rat IL-10R and CRF2–4, determine their expression in activated rat HSC in vivo and in vitro, and examine the biological responsiveness of HSC to exogenous IL-10. PCR cloning and sequencing of partial rat IL-10R and CRF2–4 cDNAs revealed 86% homology with corresponding mouse sequences. In hepatic macrophages, Northern blot with cloned IL-10R cDNA detected an expected 3.5-kb transcript, and IL-10R and CRF2–4 mRNAs showed steady constitutive expression after in vitro lipopolysaccharide treatment or cholestatic liver injury. IL-10R mRNA expression, as confirmed by immunohistochemistry, was induced 20.1- and 8.6-fold in HSC from cholestatic livers and 7-day culture-activated HSC, respectively but CRF2–4 mRNA levels were unchanged. Under serum-free conditions, IL-10 had minimal effects on collagen production but reduced DNA synthesis, matrix metalloprotease-2 mRNA levels, and activity in HSC. With serum, IL-10 inhibited both collagen production and DNA synthesis but had no effect on procollagen-α1(I) mRNA levels. This shows concomitant induction of IL-10R but not CRF2–4 to that of IL-10 by activated HSC in vitro and in vivo and associated acquisition of the responsiveness to IL-10, entailing complex effects on HSC.

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

“…This cell contains both IL10 and M6P/IGFII receptors as tested immunohistochemically. With respect to this testing, relevant parameters are TIMP-1, MMP-13, and type I collagen, because these key parameters of the fibrotic process are regulated by IL10 (Mathurin et al, 2002;Schaefer et al, 2003). In advanced liver fibrosis, a complex process resulting from an imbalance between matrix deposition and degradation leads to enhanced collagen deposition.…”

“…With regard to liver cirrhosis, IL10 is relevant because potent anti-inflammatory and antifibrotic activities of this cytokine are described. The antifibrotic effects of IL-10 are thought to be mediated by modulation of extracellular matrix deposition via a down-regulation of collagen production or up-regulation of the expression of collagenase, in particular, matrix metalloproteinase-13 (MMP-13) (Reitamo et al, 1994;Thompson et al, 1998;Wang et al, 1998;Yamamoto et al, 2001;Mathurin et al, 2002). IL10 was tested in clinical trials in patients with hepatitis C virus-induced liver fibrosis (Nelson et al, 2000(Nelson et al, , 2003, but major drawbacks related to the systemic immunosuppressive effects became apparent.…”

“…For IL10, the most relevant target cell with regard to fibrosis is the hepatic stellate cell. This is the major profibrotic cell within the liver that produces collagens, and this cell type expresses IL10 receptors (Mathurin et al, 2002;Rachmawati et al, 2004a). In vitro studies demonstrated that IL10 attenuated profibrotic activities of HSCs (Wang et al, 1998;Mathurin et al, 2002).…”

“…This is the major profibrotic cell within the liver that produces collagens, and this cell type expresses IL10 receptors (Mathurin et al, 2002;Rachmawati et al, 2004a). In vitro studies demonstrated that IL10 attenuated profibrotic activities of HSCs (Wang et al, 1998;Mathurin et al, 2002). Therefore, the pharmacokinetics of IL10 should be changed to obtain increased concentrations in this cell type to increase the antifibrotic activities of this cytokine.…”

Immune function of nonparenchymal liver cells

“…IL-10 is a negative immune regulation factor, which can inhibit the antigen presenting function of macrophages. Activated HSCs can express the IL-10 receptor, secrete IL-10, and simultaneously inhibit its activation through a negative feedback loop (Mathurin et al, 2002).…”