Journal
IMMUNOBIOLOGY
Volume 216, Issue 12, Pages 1322-1330Publisher
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2011.05.009
Keywords
Cytokines; Macrophages; LPS; TLR; TNFRp55; Yersinia enterocolitica
Categories
Funding
- Consejo Nacional de Investigaciones Cientificas y Tecnicas [PIP 6224]
- Agencia Nacional de Promocion Cientifica y Tecnologica (FONCYT) [PICT 2006-838, 2006-603, PICT 2008-763]
- National University of San Luis [PROICO 0401]
- Fundacion Roemmers
- Fundacion Sales
- Fundacion Florencio Fiorini
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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-kappa B p65 oligonucleotide antisense, indicating the involvement of TLR4-mediated NF-kappa B 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-kappa B pathways, suggesting an essential regulatory role of TNF via TNFRp55 signaling. (C) 2011 Elsevier GmbH. All rights reserved.
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