TNFRp55 modulates IL-6 and nitric oxide responses following Yersinia lipopolysaccharide stimulation in peritoneal macrophages

Immunobiology. 2011 Dec;216(12):1322-30. doi: 10.1016/j.imbio.2011.05.009. Epub 2011 May 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism
  • Cells, Cultured
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Inflammation
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism*
  • Oligodeoxyribonucleotides, Antisense / genetics
  • Polymyxin B / pharmacology
  • Prohibitins
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor Decoy Receptors / genetics
  • Tumor Necrosis Factor Decoy Receptors / immunology
  • Tumor Necrosis Factor Decoy Receptors / metabolism*
  • Yersinia enterocolitica / immunology*


  • Antigens, Bacterial
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • Oligodeoxyribonucleotides, Antisense
  • PHB2 protein, human
  • Prohibitins
  • Receptors, Tumor Necrosis Factor, Type I
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor Decoy Receptors
  • recombinant human tumor necrosis factor-binding protein-1
  • Nitric Oxide
  • Polymyxin B