No Evidence for an Involvement of the P38 and JNK Mitogen-Activated Protein in Inflammatory Bowel Diseases

Malamut, Georgia; Cabane, Candice; Dubuquoy, Laurent; Malapel, Mathilde; Dérijard, Benoı̂t; Tamboli, Cyrus; Colombel, Jean–Frédéric; Desreumaux, Pierre

doi:10.1007/s10620-006-9116-2

Cited by 24 publications

(21 citation statements)

References 39 publications

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“…We and others (19,21) have shown an upregulation of the MAPK pathway in response to TNBS instillation. Nevertheless, the role of p38 in IBD remains controversial, because its pharmacological inhibition had no effect in colitic mice (42). In the present study, we have shown that an ALA-rich formula is able to inhibit activation of NF-kB, a key transcriptional factor in the gut that regulates the inflammatory response and oxidative stress.…”

Section: Discussionmentioning

confidence: 60%

An α-Linolenic Acid-Rich Formula Reduces Oxidative Stress and Inflammation by Regulating NF-κB in Rats with TNBS-Induced Colitis ,

Hassan¹,

Ibrahim²,

Mbodji³

et al. 2010

The Journal of Nutrition

150

110

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We have previously shown that α-linolenic acid (ALA), a (n-3) PUFA exerts in vitro antiinflammatory effects in the intestine. In this study, we aimed to evaluate its effect on inflammatory and oxidative stress in a colitis model. Colitis was induced in 2 groups at d 0 by intrarectal injection of 2-4-6-trinitrobenzen sulfonic acid (TNBS), whereas the control group received the vehicle. Rats we fed 450 mg . kg(-1) . d(-1) of ALA (TNBS+ALA) while the other colitic group (TNBS) and the control group were fed an isocaloric corn oil formula for 14 d (from d -7 to d 7). RBC fatty acid composition was assessed. Oxidative stress was studied by measuring urinary 8-isoprostanes (8-IP) and colon glutathione (GSH) concentration and inducible nitric oxide synthase (iNOS) expression. Colitis was assessed histologically, by production of proinflammatory mediators, including cytokines, leukotrienes B(4) (LTB(4)), and cyclooxygenase-2 (COX-2) and by nuclear factor-κB (NF-κB) activation. The ALA-rich diet significantly increased the RBC levels of ALA, eicosapentaenoic acid, and docosapentaenoic acid (n-3) compared with the TNBS group (P < 0.01 for all). The beneficial effect of ALA supplementation on oxidative stress was reflected by lower urinary 8-IP levels (P < 0.05), a normalized colon GSH concentration (P < 0.01), and reduced colon iNOS expression (P < 0.05) compared with the TNBS group. ALA also protected against colon inflammation as assessed by lower tumor necrosis factor-α secretion and mRNA level (P < 0.05), reduced NF-κB activation (P = 0.01), and lower colon lipid mediator concentrations such as LTB(4) and COX-2 (P < 0.05) compared with the TNBS group. These findings show that an ALA-rich formula is beneficial to TNBS-induced colitic rats via inhibition of oxidative and inflammatory stress.

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Section: Discussionmentioning

confidence: 60%

An α-Linolenic Acid-Rich Formula Reduces Oxidative Stress and Inflammation by Regulating NF-κB in Rats with TNBS-Induced Colitis ,

Hassan¹,

Ibrahim²,

Mbodji³

et al. 2010

The Journal of Nutrition

150

110

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“…Previous study showed that the JNK inhibitor, SP600125, partially reduced DSS-induced wasting and colonic mucosal ulceration in mice [30], whereas another study indicated the lack of a role for JNK in IBD pathogenesis [35]. Therefore, the precise role of JNK activation in the pathogenesis of colitis is unknown.…”

Section: Discussionmentioning

confidence: 99%

Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium

Samak

Chaudhry

Gangwar

et al. 2015

Biochemical Journal

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Disruption of intestinal epithelial tight junctions is an important event in the pathogenesis of ulcerative colitis. Dextran sodium sulfate (DSS) induces colitis in mice with the symptoms similar to ulcerative colitis. However, the mechanism of DSS-induced colitis is unknown. We investigated the mechanism of DSS-induced disruption of intestinal epithelial tight junctions and barrier dysfunction in Caco-2 cell monolayers in vitro and mouse colon in vivo. DSS treatment resulted in disruption of tight junctions, adherens junctions and actin cytoskeleton leading to barrier dysfunction in Caco-2 cell monolayers. DSS induced a rapid activation of c-jun N-terminal kinase (JNK), and the inhibition or knockdown of JNK2 attenuated DSS-induced tight junction disruption and barrier dysfunction. In mice, DSS administration for 4 days caused redistribution of tight junction and adherens junction proteins from the epithelial junctions, which was blocked by JNK inhibitor. In Caco-2 cell monolayers, DSS increased intracellular Ca2+ concentration, and depletion of intracellular Ca2+ by BAPTA or thapsigargin attenuated DSS-induced JNK activation, tight junction disruption and barrier dysfunction. Knockdown of Ask1 or MKK7 blocked DSS-induced tight junction disruption and barrier dysfunction. DSS activated c-Src by a Ca2+ and JNK-dependent mechanism. Inhibition of Src kinase activity or knockdown of c-Src blocked DSS-induced tight junction disruption and barrier dysfunction. DSS increased Tyr-phosphorylation of occludin, ZO-1, E-cadherin and β-catenin. SP600125 abrogated DSS-induced Tyr-phosphorylation of junctional proteins. Recombinant JNK2 induced threonine phosphorylation and auto phosphorylation of c-Src. This study demonstrates that Ca2+-Ask1-MKK7-JNK2-cSrc signaling cascade mediates DSS-induced tight junction disruption and barrier dysfunction.

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“…However, it should be mentioned that several studies performed in mice or in tandem with human material have failed to definitively link p38 activity or expression with IBD [64,65]. These studies can possibly be reconciled with the other contradictory data as being due to different experimental set-ups.…”

Section: Therapeutic Relevance Of Map Kinase Inhibitors?mentioning

confidence: 99%

Mitogen activated protein kinases: a role in inflammatory bowel disease?

Broom

Widjaya

Troelsen

et al. 2009

Clinical and Experimental Immunology

160

114

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SummarySince their discovery more than 15 years ago, the mitogen activated protein kinases (MAPK) have been implicated in an ever-increasingly diverse array of pathways, including inflammatory signalling cascades. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by the perpetual production of inflammatory mediators. Research into the transduction pathway behind this over-production has highlighted the potential mediating role for the MAPKs and their related signalling components. This review highlights some of the research into the role for the MAPKs and their related signalling proteins in influencing the progression of IBD.

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No Evidence for an Involvement of the P38 and JNK Mitogen-Activated Protein in Inflammatory Bowel Diseases

Cited by 24 publications

References 39 publications

An α-Linolenic Acid-Rich Formula Reduces Oxidative Stress and Inflammation by Regulating NF-κB in Rats with TNBS-Induced Colitis ,

An α-Linolenic Acid-Rich Formula Reduces Oxidative Stress and Inflammation by Regulating NF-κB in Rats with TNBS-Induced Colitis ,

Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium

Mitogen activated protein kinases: a role in inflammatory bowel disease?

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