IL-1β regulates expression of Cx32, occludin, and claudin-2 of rat hepatocytes via distinct signal transduction pathways

Yamamoto, Takumi; Kojima, Takashi; Murata, Masaki; Takano, Kenichi; Go, Mitsuru; Chiba, Hideki; Sawada, Norimasa

doi:10.1016/j.yexcr.2004.06.011

Cited by 64 publications

(49 citation statements)

References 47 publications

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“…Our ultrastructural analysis indicated impairment of the blood-epithelial barrier in IKK double mutant mice. It has been shown previously that regulation of gap and tight junctions in liver cells is crucial for maintaining the blood-biliary barrier (21) and that tight-junction-related genes are regulated by inflammatory pathways in the liver (22). We showed previously that IKK1 is involved in maintaining the epidermal barrier by transcriptional regulation of tight junction proteins such as claudins (11).…”

Section: Ikk1 Regulates the Expression Of Tight Junction Proteins In mentioning

confidence: 84%

IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

Luedde

Heinrichsdorff

Lorenzi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory destruction of intrahepatic bile ducts is a common cause of vanishing bile duct syndrome and cholestasis, often progressing to biliary cirrhosis and liver failure. However, the molecular mechanisms underlying the pathogenesis of inflammatory biliary disease are poorly understood. Here, we show that the two I B kinases, IKK1/IKK␣ and IKK2/IKK␤, display distinct collaborative and specific functions that are essential to protect the liver from cytokine toxicity and bile duct disease. Combined conditional ablation of IKK1 and IKK2, but not of each kinase alone, sensitized the liver to in vivo LPS challenge, uncovering a redundant function of the two I B kinases in mediating canonical NF-B signaling in hepatocytes and protecting the liver from TNF-induced failure. Unexpectedly, mice with combined ablation of IKK1 and IKK2 or IKK1 and NEMO spontaneously developed severe jaundice and fatal cholangitis characterized by inflammatory destruction of small portal bile ducts. This bile duct disease was caused by the combined impairment of canonical NF-B signaling together with inhibition of IKK1-specific functions affecting the bile-blood barrier. These results reveal a novel function of the two I B kinases in cooperatively regulating liver immune homeostasis and bile duct integrity and suggest that IKK signaling may be implicated in human biliary diseases.cholangitis ͉ inflammation ͉ liver disease ͉ mouse models ͉ signal transduction

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Section: Ikk1 Regulates the Expression Of Tight Junction Proteins In mentioning

confidence: 84%

IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

Luedde

Heinrichsdorff

Lorenzi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, claudin-2 expression in MDCKII cells is regulated through at least two independent pathways, involving RhoA and JNK, respectively. Previous studies have indicated an involvement of the ERK pathway in the regulation of claudin-2 expression (Kinugasa et al, 2000;Lan et al, 2004;Singh and Harris, 2004;Yamamoto et al, 2004;Murata et al, 2005). However, treatment of only MDCKI, but not MDCKII cells, with the ERK inhibitor U0126 up-regulates claudin-2, suggesting that the ERK pathway is not implicated in the up-regulation of claudin-2 expression in MDCKII cells (Lipschutz et al, 2005).…”

Section: Discussionmentioning

confidence: 94%

“…The MAPK/extracellular signal-regulated kinase (ERK) kinase pathway has been implicated in the control of claudin-2 expression (Kinugasa et al, 2000;Lan et al, 2004;Singh and Harris, 2004;Yamamoto et al, 2004;Lipschutz et al, 2005;Murata et al, 2005). To investigate the role of this and other signaling pathways in the up-regulation of claudin-2 and ZO-3 in cingulin KD clones, cingulin-depleted cells were treated with either the MAPK/ERK inhibitor U0126, the p38 kinase inhibitor SB202190, or the JNK inhibitor SP600125 ( Figure 3A).…”

Section: Jnk Regulate Claudin-2 Expression Independently Of Cingulin mentioning

confidence: 99%

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Guillemot

Citi

2006

MBoC

138

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In mouse embryoid bodies, mutation of the tight junction protein cingulin results in changes in gene expression. Here, we studied the function of cingulin using a gene silencing approach in Madin-Darby canine kidney (MDCK) cells. Cingulin-depleted cells show higher protein and mRNA levels of claudin-2 and ZO-3, increased RhoA activity, activation of G 1 /S phase transition, and increased cell density. The effects of cingulin depletion on claudin-2 expression, cell proliferation, and density are reversed by coexpression of either a dominant-negative form of RhoA (RhoAN19) or the Rho-inhibiting enzyme C3 transferase. However, the increase in ZO-3 protein and mRNA levels is not reversed by inhibition of either RhoA, p38, extracellular signal-regulated kinase (ERK), or c-Jun NH 2 -terminal kinase (JNK), suggesting that cingulin modulates ZO-3 expression by a different mechanism. JNK is implicated in the regulation of claudin-2 levels independently of cingulin depletion and RhoA activity, indicating distinct roles of RhoA-and JNK-dependent pathways in the control of claudin-2 expression. Finally, cingulin depletion does not significantly alter the barrier function of monolayers and the overall molecular organization of tight junctions. These results provide novel insights about the mechanisms of cingulin function and the signaling pathways controlling claudin-2 expression in MDCK cells.

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“…4), suggesting that transcriptional down-regulation and/or accelerated mRNA degradation is the cause of their down-regulations, rather than changes in translational efficiency or altered intracellular sorting of the transporters as reported elsewhere. 31,32) A previous study reported that hepatic injury, for example lithocholic acid-or carbon tetrachloride-induced injury, results in the alteration of expression of many transporters. 33,34) IDM could also adversely induce hepatopathy as described in the package insert.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

Fujiyama

Shitara

Ito

et al. 2007

Biological & Pharmaceutical Bulletin

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Systemic administration of indomethacin (IDM) causes inflammation of the small intestine. Although the pathogenic events of IDM are more complex, it is considered that suppression of prostaglandin synthesis, mitochondrial damage and oxidative stress response are involved in it.1,2) And, generation of reactive oxygen species decreases alkaline phosphatase (ALP) activity in intestinal mucosa, followed by an attenuation of differentiation and proliferation of villus. 3,4) In addition, gram-negative bacteria-derived endotoxin also strongly induces damages of villus enterocyte and contributes to its exacerbation. 5,6) Previous studies using animal models of bowel disease involving IDM-induced intestinal injury, trinitrobenzene sulfonic acid (TNBS)-induced colitis and dextran sulfate sodium-induced colitis have shown that the enteropathy is associated with the alteration of hepatic cytochrome P450 (CYP) and been suggested the relationship of the entering bacterial endotoxin into portal vein according to an increase of intestinal epithelium permeability. [7][8][9] In contrast with CYPs, little is known about the expression of hepatic transporters in bowel injury, although drug transporters as well as metabolizing enzymes play an important role in the disposition of most drugs.Organic anion transporting polypeptides (Oatp), located in the liver sinusoidal membrane, take part in the hepatic uptake of bile acids, peptide hormones, steroid hormones and a variety of drugs.10,11) Multidrug resistance-associated protein 2 (Mrp2), located in the liver canalicular membrane, excretes a variety of organic anions including endogenous glutathione (GSH), GSH-conjugates and glucuronides into bile. 12,13) Interplay between these influx and efflux transporters is fundamental to the biliary elimination or enterohepatic recirculation of endogenous and exogenous compounds. [14][15][16] The aim of this study is to characterize the alteration in these hepatic organic anion transporters in rats with IDM-induced injury to the small intestine. The hepatic transporter function was evaluated by a pharmacokinetic study of bromosulfophthalein (BSP), and the expression of hepatic transporters for BSP was also evaluated in control and IDMtreated rats. Inflammatory mediators in the portal plasma were traced as causal candidates ultimately affecting hepatic transporter expression. MATERIALS AND METHODSChemicals IDM was purchased from Wako Pure Chemical Industries (Osaka, Japan). BSP was purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Other chemicals and solvents used were of the highest quality commercially available.In Vivo Experimental Procedures Male Sprague-Dawley rats (Japan SLC Inc., Shizuoka, Japan) weighing 235-290 g (7-8 weeks old) were used throughout the experiments. Rats were housed in an air-conditioned room (25°C) under a 12 h light-dark cycle for at least 1 week before use. Food (the MF diet, standard laboratory diet commercially available, Oriental Yeast Co., Ltd., Tokyo, Japan) and water were given ad libitum. The rats were inje...

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IL-1β regulates expression of Cx32, occludin, and claudin-2 of rat hepatocytes via distinct signal transduction pathways

Cited by 64 publications

References 47 publications

IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Down-Regulation of Hepatic Transporters for BSP in Rats with Indomethacin-Induced Intestinal Injury

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