TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus

J Immunol. 1998 Dec 1;161(11):5937-42.

Abstract

To evaluate the importance of the proinflammatory cytokines TNF and lymphotoxin-alpha (LT alpha) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LT alpha-double-deficient mice raised on the C57BL/6 background. Mice were i.v. inoculated with a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus strain, LS-1. Intravenous inoculation of a high dose of bacteria (1 x 10(7)/mouse) resulted in 67% mortality in TNF/LT alpha-deficient mice, whereas none of the controls died (p = 0.009). Those results correlated to a significantly decreased phagocytosis in vitro and inefficient bacterial clearance in vivo in mice lacking capacity to produce TNF/LT alpha. Thus, at day 6 after inoculation, S. aureus could not be found in the bloodstream of controls, but bacteremia developed in all TNF/LT alpha-deficient mice examined (p = 0.02). Interestingly, upon infection with a lower dose of staphylococci (3 x 10(6)/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-type group as compared with the TNF/LT alpha-deficient mice (40% vs 13%). Histopathologic examination revealed a lower frequency of synovitis (38% vs 90%, p < 0.05) and erosivity (25% vs 60%, NS) in TNF/LT alpha-deficient mice as compared with wild-type counterparts. Our results show the importance of TNF/LT alpha in defense against systemic S. aureus infections and point out the detrimental role of these cytokines as mediators of inflammatory response in S. aureus arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Specificity
  • Arthritis, Infectious / genetics
  • Arthritis, Infectious / immunology*
  • Arthritis, Infectious / microbiology
  • Arthritis, Infectious / mortality
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Epitopes, B-Lymphocyte / immunology
  • Immunoglobulin G / biosynthesis
  • Interferon-gamma / biosynthesis
  • Lymphocyte Activation / genetics
  • Lymphotoxin-alpha / genetics*
  • Lymphotoxin-alpha / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NZB
  • Mice, Knockout
  • Phagocytosis
  • Staphylococcal Infections / genetics
  • Staphylococcal Infections / immunology*
  • Staphylococcal Infections / microbiology
  • Staphylococcal Infections / mortality
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / immunology*
  • Staphylococcus aureus / isolation & purification
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Epitopes, B-Lymphocyte
  • Immunoglobulin G
  • Lymphotoxin-alpha
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma