Objective. To investigate patterns of synovial and systemic cytokine messenger RNA (mRNA) expression in mice with superantigen-mediated Staphylococcus aureus arthritis.Methods. Mice were inoculated intravenously with 1 X lo7 colony-forming units of toxic shock syndrome toxin-1-producing S aureus LS-1. Synovial tissues and spleens were obtained at varying time intervals after bacterial inoculation, and examined for mRNA expression of interleukin-lp (IL-lp), IL-4, IL-10, IL-12, tumor necrosis factor a (TNFa), TNFP, interferon-y (IFNy), transforming growth factor P, and perforin, by an in situ hybridization technique. Results. In situ hybridization revealed early synovial up-regulation of TNFa and IL-lj3 mRNA expression. Peak frequencies of these proinflammatory cytokines were observed at the second and third week of the infection. Expression of T cell-derived cytokine mRNAs was detected later, and in a relatively low frequency. Notably, induction and peak numbers of Th2 cytokine (IL-4 and IL-10) mRNA expression preceded Thl cytokine (IFNy and TNFP) mRNAs. In comparison with synovial tissues, peak spleen cytokine mRNA expression of IL

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Tumor necrosis factor (TNF) has generally been regarded as a protective cytokine in host defense against bacterial infections. In the present study, we evaluated the role of TNF in the acute phase of infection by Yersinia enterocolitica by using mice rendered genetically deficient in TNF receptor p55 (TNFRp55؊/؊ mice showed more effective resistance to the bacteria, reflected in enhanced bacterial clearance and less tissue damage, than did control C57BL/6 mice. C57BL/6 mice showed evidence of extensive apoptosis in the spleen accompanied by a selective decrease in the CD4 ؉ -T-cell population of splenocytes, whereas TNFRp55 ؊/؊ mice were spared these changes. The splenocytes from TNFRp55 ؊/؊ mice also maintained a robust gamma interferon IFN-␥ response to mitogenic stimulation, while the comparable response in C57BL/6 mice was impaired. In addition, splenocytes harvested from infected mice demonstrated lower production of interleukin-10 IL-10 in TNFRp55؊/؊ mice than in C57BL/6 mice. These findings suggest that Yersinia can induce TNFRp55-mediated apoptosis of splenocytes in the acute phase of the infection and that alteration of T-cell-generated cytokines can dramatically alter the early events in host defense against this pathogen.

Objective. To dissect the host defense mechanisms in relation to the development of Yersiniaassociated arthritis by evaluating the impact of tumor necrosis factor receptor p55 (TNFRp55) deficiency on Yersinia enterocolitica infection.Methods. TNFRp55؊/؊ and C57BL/6 mice were inoculated intravenously with arthritogenic strain 8081 of Y enterocolitica serotype 0:8. Mice were observed daily for generating survival curves and monitoring arthritis. In subsequent sets of experiments, mice were sacrificed at day 14 after infection for examination of histopathology of joints, bacterial clearance, macrophage microbicidal activity, nitric oxide (NO) production, oxidative burst generation, and cytokine production.Results. There was an 80% mortality rate in TNFRp55؊/؊ mice compared with 25% in the controls at 8 weeks after inoculation with 70 colony-forming units of Y enterocolitica 0:8. Histologic examination of joint tissues revealed that TNFRp55؊/؊ mice developed more severe arthritis, including cartilage degradation and bony destruction, than controls at day 14 after infection. The more extensive joint pathology in TNFRp55؊/؊ mice was correlated with the higher bacterial load in liver, spleen, and lungs, and with the increased levels of interleukin-10. TNFRp55؊/؊ mice displayed impaired intracellular killing of bacteria by macrophages. This was associated with decreased NO production and impaired oxidative burst activity.Conclusion. This study demonstrates that TNF signaling through TNFRp55 controls the severity of Yersinia-induced arthritis and implicates TNF-mediated macrophage microbicidal activity as a central event in this process.