title: 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.
abstract: LeIF, a gene homologue of the eukaryotic initiation factor 4A was first described as a leishmanial antigen that induced a Th1-type T cell response 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 the effects of LeIF on cytokine production and expression of surface molecules by normal human monocytes as well as by monocyte-derived macrophages and dendritic cells (MoDC). LeIF was a strong inducer of IL-12 and, to a lesser extent, of IL-10 and tumor necrosis factor (TNF)-alpha in macrophages and MoDC. IL-12 production did not require CD40 triggering, confirming that the ability of LeIF to induce IL-12 was not mediated through an effect on T cells. However, addition of soluble CD40 ligand (L) synergistically augmented IL-12 production in macrophages and MoDC. The cytokine-inducing activity of LeIF is located in the N-terminal portion of the molecule and was both proteinase K sensitive and polymyxin B resistant. LeIF, lipopolysaccharide and fixed Staphylococcus aureus all induced comparable amounts of IL-12, validating the potent cytokine-inducing effects of LeIF. Moreover, of these stimuli, LeIF had the highest IL-12/IL-10 and IL-12/TNF-alpha ratio demonstrating the preference of LeIF for IL-12 induction. Studies investigating the expression of surface molecules showed that LeIF up-regulated B7-1 and CD54 (ICAM-1) on macrophages and MoDC. To our knowledge this is the first 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.
authors.affiliation: Infectious Disease Research Institute, Seattle, WA, USA. probst@corixa.com
authors.forename: P
authors.initials: P
authors.lastname: Probst
authors.forename: Y A
authors.initials: YA
authors.lastname: Skeiky
authors.forename: M
authors.initials: M
authors.lastname: Steeves
authors.forename: A
authors.initials: A
authors.lastname: Gervassi
authors.forename: K H
authors.initials: KH
authors.lastname: Grabstein
authors.forename: S G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000378:metabolism; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D023201:CD40 Ligand; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; C092810:LeIF protein, Leishmania; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010448:Peptide Initiation Factors; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12