Modulation of In Vitro Monocyte Cytokine Responses to Leishmania donovani Interferon-'y Prevents Parasite-induced Inhibition of Interleukin I Production and Primes Monocytes

Cytokines produced by mononuclear cells are important regulatory and effector molecules and evidence has been presented to support a role at least for tumor necrosis factor-a (TNF-a) and interferon-y (IFN-y) in host defense against Leishmania. In the present study, we examined the production of TNF-a and interleukin 1 (IL-I) by resting and IFN-y-primed peripheral blood monocytes infected in vitro with Leishmania donovani. Monocytes produced neither IL-1 nor TNF-a during challenge with Leishmania. Cells preinfected with Leishmania synthesized normal amounts of TNF-a, but had diminished production of IL-I in response to stimulation with either S. aureus or lipopolysaccharide (LPS). The induction by S. aureus or LPS of IL-1jt mRNA accummulation in infected cells was normal despite diminished intracellular or supernatant IL-I protein and bioactivity. Thus, inhibition of IL-i production by Leishmania most probably reflected diminished translation of IL-1ft mRNA. Pretreatment of cells with IFN--y abrogated infection-induced inhibition of IL-i production and primed cells for the production of both IL-i and TNF-a upon subsequent exposure to Leishmania. These results indicate that L. donovani has evolved the capacity to infect mononuclear phagocytes, without stimulating the production of two potentially host-protective monokines. The ability of IFN-'y to prime monocytes to produce TNF-a and IL-1 in response to infection with Leishmania and to prevent inhibition of IL-i production may have implications for immunotherapy with this lymphokine. (J. Clin. Invest. 1990. 85:1914-1924.) Leishmania * monocytes * monokines interferon-v