Posttranscriptional regulation of connexin 32 expression in liver during acute inflammation

Abstract

Gap junctions mediate the communication between adjacent cells in tissues. In the liver, connexin 32 (Cx32) subunits make up the predominating gap junctions. The expression of Cx32 gene has been observed to be down-regulated in response to inflammatory states and during liver regeneration. In the present study we attempt to elucidate the molecular mechanisms underlying the down-regulation of the Cx32 expression during acute inflammation. A decrease in the level of Cx32 mRNA in rat liver occurred between 3 and 6 h after intravenous administration of bacterial lipopolysaccharide (LPS), simultaneously with the induction of an acute inflammatory response characterized by an increase in the level for beta-fibrinogen and a reduction of phosphoenolpyruvate carboxykinase mRNA. The reduction in Cx32 steady-state mRNA levels appears to occur at the posttranscriptional level, since the rate of degradation of this message seems to be higher than the rate of transcription of the gene. Degradation of Cx32 mRNA was blocked by the administration of actinomycin D, but not by cycloheximide, prior to injection of LPS. The stabilization of Cx32 message by actinomycin D correlated with the preservation of Cx32 on the cell surface, which otherwise disappears after administration of LPS alone. These results suggest that cellular communication via gap junctions could be regulated at the level of gene expression, by a posttranscriptional mechanism, during acute inflammatory states.

Differential regulation of gap junctions by proinflammatory mediators in vitro.

“…Previous data has shown that LPS can affect posttranscriptional regulation of Cx32 in the rat liver (12). In this study, we demonstrate for the first time that these proinflammatory mediators are also capable of suppressing functional human myoendothelial GJIC in vitro.…”

“…There are a few reports suggesting that some proinflammatory mediators are involved in the regulation of GJIC (10)(11)(12). Bacterial lipopolysaccharide (LPS) has been shown to cause induction of Cx43 expression in hamster leukocytes in vitro (11), and to alter posttranscriptional regulation of Cx32 gene expression in rat liver during acute inflammation (12).…”

“…Bacterial lipopolysaccharide (LPS) has been shown to cause induction of Cx43 expression in hamster leukocytes in vitro (11), and to alter posttranscriptional regulation of Cx32 gene expression in rat liver during acute inflammation (12). IL-1 ␣ was shown to suppress GJIC in human endothelial cells (10).…”

Inflammatory conditions induce gap junctional communication between rat Kupffer cells both in vivo and in vitro

“…Cx32 and Cx26, two parenchymal cells Cxs, are reduced in acute liver inflammation induced by LPS (5,(23)(24)(25)(26), hepatic ischemia/ reperfusion (25), and cholestasis caused by common bile duct ligation (5,27). Under these conditions the expression of Cx43 by KCs, non-parenchymal cells, is enhanced to clear/repair the damage.…”

Modifications in Connexin Expression in Liver Development and Cancer

“…hepatitis, fi brosis and cirrhosis) as well as during hepatotoxicity (Nakashima et al, 2004;Nakata et al, 1996;Yamaoka et al, 2000). This is equally refl ected at the posttranscriptional level and is caused by increased degradation of Cx32 mRNA molecules (Gingalewski et al, 1996). Although a downregulation in protein content is hereby also seen for Cx26, its mRNA amounts are not affected and even increase in infl ammatory conditions (De Maio et al, 2000).…”