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Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-?B-inducible immune pathways.

ABSTRACT: Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-? and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-?B p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-? and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO-EPOR interaction decreases the production of NF-?B-inducible immune mediators, thus limiting tissue damage and ameliorating disease severity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases.

SUBMITTER: Nairz M

PROVIDER: S-EPMC3032045 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-κB-inducible immune pathways.

Nairz Manfred M Schroll Andrea A Moschen Alexander R AR Sonnweber Thomas T Theurl Milan M Theurl Igor I Taub Nicole N Jamnig Christina C Neurauter Daniela D Huber Lukas A LA Tilg Herbert H Moser Patrizia L PL Weiss Günter G

Immunity 20110120 1

Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-α and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-κB p65 activation by EPO. Accordingly, in systemic Salmo ...[more]

PMID: 21256055

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Project description:Background and purposeKalopanaxsaponin A, a triterpenoid saponin isolated from Kalopanax pictus (family Araliaceae), potently inhibited nuclear factor-kappa B (NF-κB) activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages during a screening programme for anti-colitis agents from natural products. Its anti-inflammatory mechanism remains unknown. Therefore, we investigated its anti-inflammatory effects in lipopolysaccharide (LPS)- or peptidoglycan-stimulated murine peritoneal macrophages and trinitrobenzene sulphonic acid (TNBS)-induced colitic mice.Experimental approachPeritoneal macrophages from male ICR mice were stimulated with LPS or peptidoglycan in vitro and treated with kalopanaxsaponin A. Colitis was induced in vivo by intrarectal administration of TNBS in male ICR mice. Mice were treated daily with kalopanaxsaponin A, sulphasalazine or phosphate-buffered saline. Inflammatory markers, cytokines, enzymes and transcription factors were measured by ELISA, immunoblot, flow cytometry and immunofluorescent confocal microscopy.Key resultsKalopanaxsaponin A potently inhibited the expression of the pro-inflammatory cytokines, interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6, induced by LPS, but not that induced by TNF-α, in peritoneal macrophages. However, it potently increased the expression of the anti-inflammatory cytokine IL-10. Kalopanaxsaponin A inhibited activation of the IL-1 receptor-associated kinase (IRAK)-1, inhibitor of κB kinase-β, NF-κB and mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun NH(2) -terminal kinase, p-38), but LPS/Toll-like receptor-4 interaction and IRAK-4 activation were not affected. Oral administration of kalopanaxsaponin A (10 and 20 mg·kg(-1) ) improved the clinical parameters and histology in vivo. Kalopanaxsaponin A inhibited NF-κB and mitogen-activated protein kinase activation induced by TNBS by suppressing IRAK-1 activation.Conclusions and implicationsKalopanaxsaponin A may improve inflammatory diseases, such as colitis, by inhibiting IRAK-1 activation.

Project description:Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment strategy, considering the potential adverse effects of synthetic drugs used to treat UC. Kaempferol (Kae) is an anti-inflammatory and antioxidant flavonoid derived from a variety of medicinal plants. In this study, we determined the efficacy and mechanism of action of Kae as an anti-UC agent in dextran sulfate sodium (DSS)-induced colitis mice. DSS challenge in a mouse model of UC led to weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by pretreatment with Kae. In addition, intestinal permeability was shown to improve using fluorescein isothiocyanate (FITC)-dextran administration. DSS-induced destruction of the intestinal barrier was also significantly prevented by Kae administration via increases in the levels of ZO-1, occludin, and claudin-1. Furthermore, Kae pretreatment decreased the levels of IL-1β, IL-6, and TNF-α and downregulated transcription of an array of inflammatory signaling molecules, while it increased IL-10 mRNA expression. Notably, Kae reshaped the intestinal microbiome by elevating the Firmicutes to Bacteroidetes ratio; increasing the linear discriminant analysis scores of beneficial bacteria, such as Prevotellaceae and Ruminococcaceae; and reducing the richness of Proteobacteria in DSS-challenged mice. There was also an evident shift in the profile of fecal metabolites in the Kae treatment group. Serum LPS levels and downstream TLR4-NF-κB signaling were downregulated by Kae supplementation. Moreover, fecal microbiota transplantation from Kae-treated mice to the DSS-induced mice confirmed the effects of Kae on modulating the gut microbiota to alleviate UC. Therefore, Kae may exert protective effects against colitis mice through regulating the gut microbiota and TLR4-related signaling pathways. This study demonstrates the anti-UC effects of Kae and its potential therapeutic mechanisms, and offers novel insights into the prevention of inflammatory diseases using natural products.

Dataset Information

Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-?B-inducible immune pathways.

Publications

Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-κB-inducible immune pathways.

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