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Staphylococcus aureus-Induced Septic Arthritis and Septic Death Is Decreased in IL-4-Deficient Mice: Role of IL-4 as Promoter for Bacterial Growth

Olof Hultgren^*, Manfred Kopf and Andrzej Tarkowski^*

^* Department of Rheumatology, University of Göteborg, Göteborg, Sweden; and Basel Institute for Immunology, Basel, Switzerland

Lack of IL-4 has been shown to be protective in some experimental models of infectious diseases in mice such as cutaneous leishmaniasis. At the same time IL-4, together with other Th2 cytokines, including IL-10 and IL-13, is known as an anti-inflammatory cytokine with the potential to down-regulate proinflammatory cytokine production. To investigate the role of IL-4 in experimental Staphylococcus aureus-induced and T lymphocyte-mediated arthritis, IL-4-deficient C57BL/6 mice (IL-4^-/-) and their congenic controls (IL-4^+/+) were inoculated with a toxic shock syndrome toxin-1-producing S. aureus strain. In IL-4^+/+ mice, arthritis peaked 14 days after bacterial inoculation, whereas, at that time, IL-4^-/- mice displayed significantly less frequent (p < 0.05) joint inflammation. Paralleling lower frequency of arthritis, IL-4-deficient mice showed a decreased bacterial burden in joints (p = 0.014) and kidneys (p = 0.029), as well as lower infection-triggered weight decrease and mortality. In vitro, IL-4 inhibited intracellular killing of S. aureus in infected macrophages, without affecting phagocytosis. This finding may explain the enhanced staphylococcal clearance observed in IL-4^-/- mice in vivo. Our results suggest that IL-4 and IL-4-dependent Th2 responses promote septic arthritis and sepsis-related mortality by inhibition of bacterial clearance during S. aureus infection.

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