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Disseminated Mycobacterium avium infection is the most frequent bacterial infection in patients with advanced AIDS and also associated with interferon-gamma (IFN-γ) or IL-12 receptor deficiency. IFN-γ is a key cytokine in host defence against M. avium infection. Expression of IL-18, a potent IFN-γ inducer, and IFN-γ by human monocytes after infection with M. avium was examined. Monocytes were co-cultured with isogenic smooth-transparent (SmT: virulent) or smooth-domed (SmD: avirulent) M. avium strains (10 organisms per monocyte). Infection with the SmD strain induced significantly higher concentration of IL-18 and IFN-γ in culture supernatants than did the SmT strain. IFN-γ production in response to M. avium was partially inhibited by anti-human IL-18 MoAb. Both recombinant human IL-12 (77 ± 42 pg/ml, control versus 1492 ± 141 pg/ml, cultures with IL-12 1 ng/ml) and IL-18 (126 ± 37 pg/ml, control versus 2683 ± 864 pg/ml, cultures with IL-18 10 ng/ml) augmented M. avium-induced IFN-γ production. Freshly isolated uninfected monocytes expressed constitutive levels of IL-18. Following infection with M. avium, enhancement of IL-18 mRNA expression peaked at 3–6 h. IL-18 protein was detected in monocyte lysates as early as 1 h after infection with both SmT and SmD M. avium strains by Western blotting. Higher IL-18 expression by monocytes infected with the avirulent strain may result in more IFN-γ production, thus modulating its pathogenicity. Local induction of IL-18 may be important both for M. avium pathogenicity and host defence and become a potential candidate for immunotherapy.