IL-1beta regulates expression of Cx32, occludin, and claudin-2 of rat hepatocytes via distinct signal transduction pathways.
The functions of gap and tight junctions are perturbed during the acute-phase response to liver injury. To elucidate the mechanism of pro-inflammatory cytokine IL-1beta responsible for regulation of hepatic gap and tight junctions, we analyzed expression and function of gap and tight junctions using a rat liver injury model and primary cultures of rat hepatocyte. In rat liver lobules at 24 h after thioacetamide (TAA) treatment, where some IL-1beta-positive non-parenchymal cells existed, disappearance of connexin32-positive spots at cell borders of the hepatocytes and increases of claudin-2 and occludin immunoreactivities in bile canalicular regions were observed. In primary cultures of rat hepatocytes, IL-1beta caused the disappearance of connexin32, which was reciprocal to the induction and localization of claudin-2 to cell membranes. The downregulated connexin32 expression was inhibited by treatment with a MAP-kinase inhibitor (PD98059), whereas the upregulated claudin-2 expression was blocked by p38 MAP and PI3-kinase inhibitors (SB203580 and LY294002). The changes of connexin32 and claudin-2 may be controlled at the transcriptional level via NF-kappaB, HNF-1alpha, and CDX2. Occludin was hyperphosphorylated by IL-1beta treatment and was inhibited by treatment with a PI3-kinase inhibitor. These results demonstrate that MAP-kinase, p38 MAP-kinase, and PI3-kinase are distinctly involved in the regulation of hepatic gap and tight junctions during the acute-phase response to IL-1beta.[1]References
- IL-1beta regulates expression of Cx32, occludin, and claudin-2 of rat hepatocytes via distinct signal transduction pathways. Yamamoto, T., Kojima, T., Murata, M., Takano, K., Go, M., Chiba, H., Sawada, N. Exp. Cell Res. (2004) [Pubmed]
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