TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus.
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.
Hultgren
O
O
Department of Rheumatology, University of Göteborg, Sweden. olof.hultgren@immuno.gu.se
Eugster
H P
HP
Sedgwick
J D
JD
Körner
H
H
Tarkowski
A
A
D000818:Animals; D000918:Antibody Specificity; D001170:Arthritis, Infectious / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D010587:Phagocytosis; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology* / Q000302:isolation & purification; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
D018985:Epitopes, B-Lymphocyte; D007074:Immunoglobulin G; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma