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 ly mphotoxin-alpha (LT alpha) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LT alpha-double-deficient mic e raised on the C57BL/6 background, Mice were i.v. inoculated with a t oxic 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 signi ficantly decreased phagocytosis in vitro and inefficient bacterial cle arance 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 blood stream of controls, but bacteremia developed in all TNF/LT alpha-defic ient mice examined (p = 0.02). Interestingly, upon infection with a lo wer dose of staphylococci (3 x 10(6)/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-typ e 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-d eficient mice as compared with wild-type counterparts, Our results sho w the importance of TNF/LT alpha in defense against systemic S, aureus infections and point out the detrimental role of these cytokines as m ediators of inflammatory response in S, aureus arthritis.