Resistin-like molecule β regulates innate colonic function: Barrier integrity and inflammation susceptibility

Hogan, Simon P.; Seidu, Luqman; Blanchard, Carine; Groschwitz, Katherine; Mishra, Anil; Karow, Margaret; Ahrens, Richard; Artis, David; Murphy, Andrew J.; Valenzuela, David M.; Yancopouloš, George D.; Rothenberg, Marc E.

doi:10.1016/j.jaci.2006.04.039

Cited by 138 publications

(164 citation statements)

References 43 publications

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“…To verify proteolytic activity in the CCC, we incubated CCC with a C. jejuni model glycoprotein, CmeA (29,30). Immunoblotting demonstrated complete degradation of CmeA by both 1-week and 5-week CCC within 1 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

N-Glycosylation of Campylobacter jejuni Surface Proteins Promotes Bacterial Fitness

et al. 2013

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bCampylobacter jejuni is the etiologic agent of human bacterial gastroenteritis worldwide. In contrast, despite heavy colonization, C. jejuni maintains a commensal mode of existence in chickens. The consumption of contaminated chicken products is thought to be the principal mode of C. jejuni transmission to the human population. C. jejuni harbors a system for N-linked protein glycosylation that has been well characterized and modifies more than 60 periplasmic and membrane-bound proteins. However, the precise role of this modification in the biology of C. jejuni remains unexplored. We hypothesized that the N-glycans protect C. jejuni surface proteins from the action of gut proteases. The C. jejuni pglB mutant, deficient in the expression of the oligosaccharyltransferase, exhibited reduced growth in medium supplemented with chicken cecal contents (CCC) compared with that of wild-type (WT) cells. Inactivation of the cecal proteases by heat treatment or with protease inhibitors completely restored bacterial viability and partially rescued bacterial growth. Physiological concentrations of trypsin, but not chymotrypsin, also reduced C. jejuni pglB mutant CFU. Live or dead staining indicated that CCC preferentially influenced C. jejuni growth as opposed to bacterial viability. We identified multiple chicken cecal proteases by mass fingerprinting. The use of protease inhibitors that target specific classes indicated that both metalloproteases and serine proteases were involved in the attenuated growth of the oligosaccharyltransferase mutant. In conclusion, protein N-linked glycosylation of surface proteins may enhance C. jejuni fitness by protecting bacterial proteins from cleavage due to gut proteases.

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Section: Resultsmentioning

confidence: 99%

N-Glycosylation of Campylobacter jejuni Surface Proteins Promotes Bacterial Fitness

et al. 2013

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“…The transcriptional program induced through the Ikke-Akt pathway in Apc-mutated IECs remains unclear. One candidate could be Retn1b, which is upregulated in colon cancer, and protects against parasitic helminth infections by maintaining the colonic barrier function (42)(43)(44). Retn1b expression is induced through IL23 and Akt in intestinal goblet cells (45).…”

Section: Discussionmentioning

confidence: 99%

The Prosurvival IKK-Related Kinase IKKϵ Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine

et al. 2016

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Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9);

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“…It is involved in regulating intestinal homeostasis [124,125]. When secreted extracellularly, it can act as a regulatory molecule in luminal molecule recognition and transportation across the epithelial barrier and has been shown to bind to nematodes and to possess anti-chemotactic activity against the parasites.…”

Section: Resistin and Inflammatory Bowel Diseasesmentioning

confidence: 99%

The role of resistin as a regulator of inflammation: Implications for various human pathologies

Filková

Haluzı́k

Šenolt

2009

Clinical Immunology

359

297

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Resistin-like molecule β regulates innate colonic function: Barrier integrity and inflammation susceptibility

Abstract: Background: Resistin-like molecule (RELM) β is a cysteine-rich cytokine expressed in the gastrointestinal tract and implicated in insulin resistance and gastrointestinal nematode immunity; however, its function primarily remains an enigma.

Cited by 138 publications

References 43 publications

N-Glycosylation of Campylobacter jejuni Surface Proteins Promotes Bacterial Fitness

N-Glycosylation of Campylobacter jejuni Surface Proteins Promotes Bacterial Fitness

The Prosurvival IKK-Related Kinase IKKϵ Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine

The role of resistin as a regulator of inflammation: Implications for various human pathologies

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