ENHANCEMENT OF INTRACELLULAR REPLICATION OF TOXOPLASMA-GONDII BY IL-6- INTERACTIONS WITH IFN-GAMMA AND TNF-ALPHA

Toxoplasma gondii is a major pathogen of immunocompromised hosts, and one defense mechanism against the parasite is activation of macrophage s (M phi) for toxoplasmacidal activity by IFN-gamma after triggering b y TNF-alpha. IL-6, IFN-gamma, and TNF-alpha are cytokines involved in inflammatory responses and are induced by T. gondii infection. We stud ied the interaction of these three cytokines using an in vitro model o f T. gondii infection. Pretreatment (but not post-treatment) of unelic ited murine peritoneal M phi with IL-6 enhanced T. gondii replication in a dose-dependent manner. Pretreatment with IFN-gamma resulted in ac tive killing of parasites whereas the addition of IL-6 to IFN-gamma pr etreatment resulted in a reversal of IFN-gamma-mediated toxoplasmacida l activity. Combining TNF-alpha with IL-6 and IFN-gamma pretreatment r esulted in restoration of toxoplasmacidal activity. Addition of a poly clonal anti-TNF-alpha Ab to IL-6 and IFN-gamma pretreatment resulted i n enhancement in the IL-6-mediated impairment of IFN-gamma function. T hese data taken together suggest that IL-6 enhances intracellular repl ication of T. gondii and reverses IFN-gamma mediated activation of mur ine peritoneal M phi, and that certain of the interactions between the se two cytokines may be at the level of TNF-alpha triggering.