title: TNFRp55 modulates IL-6 and nitric oxide responses following Yersinia lipopolysaccharide stimulation in peritoneal macrophages.
abstract: While cytokines are major regulators of macrophage activation following host-pathogen interactions, they also act to limit inflammation to avoid tissue damage. In previous studies we reported the development of progressive Yersinia enterocolitica-induced reactive arthritis (ReA) in mice lacking the tumor necrosis factor receptor p55 (TNFRp55). In this work, we analyzed the response of TNFRp55⁻/⁻ macrophages to Y. enterocolitica antigens. We found higher concentration of nitric oxide (NO) in TNFRp55⁻/⁻ compared to wild-type macrophages in response to heat-killed Yersinia (HKY) and Yersinia outer membranes (OM). Moreover, Toll-like receptor (TLR)4 expression was increased in OM-stimulated TNFRp55⁻/⁻ versus wild-type (WT) macrophages. Accordingly, NO production was inhibited in TLR4-deficient macrophages following stimulation with OM, suggesting that LPS may function as a major OM component implicated in these responses. Thus, augmented NO production together with enhanced expression of inducible nitric oxide synthase (iNOS) and higher IL-6 production, may provide a pro-inflammatory setting in Yersinia LPS-stimulated TNFRp55⁻/⁻ macrophages. Augmented synthesis of NO and IL-6 was prevented by treatment with Polymyxin B, or by exposure to a specific NF-κB p65 oligonucleotide antisense, indicating the involvement of TLR4-mediated NF-κB activation in the unleashed pro-inflammatory response triggered by TNFRp55 deficiency. Thus, TNFRp55 modulates macrophage functions in response to Yersinia LPS stimulation through mechanisms involving NO, IL-6 and NF-κB pathways, suggesting an essential regulatory role of TNF via TNFRp55 signaling.
authors.affiliation: Division of Immunology, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, San Luis, Argentina.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Eliçabe
authors.forename: José L
authors.initials: JL
authors.lastname: Arias
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.forename: María Silvia
authors.initials: MS
authors.lastname: Di Genaro
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D011112:Polymyxin B / Q000494:pharmacology; D000091402:Prohibitins; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015008:Yersinia enterocolitica / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; C000717331:PHB2 protein, human; D000091402:Prohibitins; D047888:Receptors, Tumor Necrosis Factor, Type I; D051197:Toll-Like Receptor 4; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D009569:Nitric Oxide; D011112:Polymyxin B