title: IL-1beta regulates expression of Cx32, occludin, and claudin-2 of rat hepatocytes via distinct signal transduction pathways.
abstract: 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.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.forename: Masaki
authors.initials: M
authors.lastname: Murata
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takano
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Go
authors.forename: Hideki
authors.initials: H
authors.lastname: Chiba
authors.forename: Norimasa
authors.initials: N
authors.lastname: Sawada
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D057167:Claudins; D017630:Connexins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D062793:Occludin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013853:Thioacetamide / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000097002:Gap Junction beta-1 Protein
chemical_list: D000071616:CDX2 Transcription Factor; D057167:Claudins; D017630:Connexins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D007375:Interleukin-1; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D062793:Occludin; D019869:Phosphatidylinositol 3-Kinases; D013853:Thioacetamide; D014157:Transcription Factors; D000097002:Gap Junction beta-1 Protein; C487514:Cdx2 protein, mouse; C113371:Cldn2 protein, mouse; C491874:Cldn2 protein, rat; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C568986:Ocln protein, mouse; C568987:Ocln protein, rat