A LEISHMANIA PROTEIN THAT MODULATES INTERLEUKIN (IL)-12, IL-10 AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION AND EXPRESSION OF B7-1 IN HUMAN MONOCYTE-DERIVED ANTIGEN-PRESENTING CELLS

LeIF, a gene homologue of the eukaryotic initiation factor 4A was firs t described as a leishmanial antigen that induced a Th1-type T cell re sponse in peripheral blood mononuclear cells (PBMC) from leishmaniasis patients. Moreover, the interferon (IFN)-gamma production by PBMC was found to be interleukin (IL)-12 dependent. Herein, we characterize th e effects of LeIF on cytokine production and expression of surface mol ecules by normal human monocytes as well as by monocyte-derived macrop hages and dendritic cells (MoDC). LeIF was a strong inducer of IL-12 a nd, to a lesser extent, of IL-10 and tumor necrosis factor (TNF)-alpha in macrophages and MoDC. IL-12 production did not require CD40 trigge ring, confirming that the ability of LeIF to induce IL-12 was not medi ated through an effect on T cells. However, addition of soluble CD40 l igand (L) synergistically augmented IL-12 production in macrophages an d MoDC. The cytokine-inducing activity of LeIF is located in the N-ter minal portion of the molecule and was both proteinase K sensitive and polymyxin B resistant. LeIF, lipopolysaccharide and fixed Staphylococc us aureus all induced comparable amounts of IL-12, validating the pote nt cytokine-inducing effects of LeIF Moreover, of these stimuli, LeIF had the highest IL-12/IL-10 and IL-12/TNF-alpha ratio demonstrating th e preference of LeIF for IL-12 induction. Studies investigating the ex pression of surface molecules showed that LeIF up-regulated B7-1 and C D54 (ICAM-1) on macrophages and MoDC. To our knowledge this is the fir st report describing IL-12 production, up-regulation of co-stimulatory and intercellular adhesion molecules by monocytic antigen-presenting cells in response to a protein from a pathogenic microorganism. These immunomodulatory characteristics of LeIF might be excellent properties for a Th1-type adjuvant.