Rho kinase blockade prevents inflammation via nuclear factor κB inhibition: evidence in Crohn’s disease and experimental colitis

Segain, Jean–Pierre; Blétière, Diane Raingeard de la; Sauzeau, Vincent; Bourreille, Arnaud; Hilaret, Grégory; Cario‐Toumaniantz, Chrystelle; Pacaud, Pierre; Galmiche, Jean–Paul; Loirand, Gervaise

doi:10.1016/s0016-5085(03)00283-x

Cited by 179 publications

(158 citation statements)

References 30 publications

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“…4F) abrogated LGR5-induced reporter activity. It has been suggested that NF-κB is a link between inflammation and tumor development induced by the Rho signaling pathway (Benitah et al, 2003;Karin et al, 2002;Lin and Karin, 2003;Segain et al, 2003). In addition, NF-κB plays a role in the regulation of stem cell self-renewal and differentiation (Schugar et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach.LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα 12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G 12/13 signaling.

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Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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“…Although the latter study did not investigate the effects of pravastatin on Rho protein activation in the colon, increased activation of RhoA has been found both in inflamed intestinal mucosa of IBD patients and in the colons of rats with trinitrobenzenesulfonic acidinduced colitis (121). Use of Y-27632 to inhibit Rho kinase significantly reduces colonic inflammation in rats with experimental colitis by preventing NF-B activation.…”

Section: Abeles and Pillingermentioning

confidence: 96%

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Abeles

Pillinger

2006

Arthritis & Rheumatism

136

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“…Recently, it was also shown that NF-kb activation is directly regulated by the Rho/Rho-kinase pathway. 25,26 Thus, in this study, constitutive inhibition of NF-kb by DNRhoK might have inhibited the production of pro-inflammatory cytokines and time-dependent inflammatory response after reperfusion.…”

Section: Involvement Of Rho-kinase In Cold Ischemia/ Reperfusion-indumentioning

confidence: 63%

“…17,22,23 Indeed, we have also recently demonstrated that Rhokinase is involved in the ROS production in the hyperacute phase of the reperfusion and pro-inflammatory cytokine production in hepatic I/R injury in rats in vivo. 24 Furthermore, previous reports including ours 25,26 show that Rho-kinase can regulate NF-kb activation through IkB phosphorylation in inflammatory responses. However, it is unknown whether Rho-kinase is directly involved in the intracellular signal transduction to produce ROS in vivo in the hyperacute phase of reperfusion.…”

Section: Introductionmentioning

confidence: 81%

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Rho-kinase as a novel gene therapeutic target in treatment of cold ischemia/reperfusion-induced acute lethal liver injury: effect on hepatocellular NADPH oxidase system

et al. 2007

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In the transplant surgery, reactive oxygen species (ROS) from the reperfused tissue cause ischemia-reperfusion injury, resulting in the primary graft failure. We have recently reported that Rho-kinase, an effecter of the small GTPase Rho, plays an important role in the ROS production in the hyperacute phase of reperfusion; however, the sources and mechanisms of the ROS production remain to be elucidated. The aim of this study was to investigate the source of ROS production with a special reference to Rho-kinase to develop a new strategy against ischemia-reperfusion injury. In an in vivo rat model of liver transplantation, Kupffer cells in the graft were depleted using liposome-encapsulated dichloromethylene diphosphonate to examine the source of ROS production. The effect of adenoviral-mediated overexpression of a dominant-negative Rho-kinase (AdDNRhoK) in hepatocytes in the graft was also examined. Kupffer cells were not involved in the ROS production, whereas the AdDNRhoK transfection to hepatocytes significantly suppressed the ROS production. Furthermore, the ROS production was dose-dependently inhibited by apocynin, an NADPH oxidase inhibitor. Expression of DNRhoK also suppressed the release of pro-inflammatory cytokines, and ameliorated the lethal liver injury with a significant prolongation of the survival. These results suggest that the Rho-kinase-mediated pathway plays a crucial role in the ROS production through NADPH oxidase in hepatocytes during the hyperacute phase of reperfusion in vivo. Thus, Rhokinase in hepatocytes may be a new therapeutic target for the prevention of primary graft failure in liver transplantation.

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Rho kinase blockade prevents inflammation via nuclear factor κB inhibition: evidence in Crohn’s disease and experimental colitis

Cited by 179 publications

References 30 publications

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Rho-kinase as a novel gene therapeutic target in treatment of cold ischemia/reperfusion-induced acute lethal liver injury: effect on hepatocellular NADPH oxidase system

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