ABSTRACT
The shift to the production of a Th1 cytokine profile during an intracellular infection has been shown to depend on antigen presenting cells-derived IL-12 and T-cell-derived IFN-gamma production. IL-18 facilitates Th1 priming in synergy with IL-12 through the stimulation of IFN-gamma production by T cells, B cells, NK cells, macrophages and DCs. A low level of IFN-gamma production in PBMC cultures from lepromatous leprosy patients (LL) has been previously reported by several groups. We evaluated the synthesis of this cytokine after exogenous addition of recombinant IL-12 and IL-18 (IL12/IL18) in order to induce recovery of the IFN-gamma levels with Mycobacterium leprae antigenic stimulation. The aim of this study was to investigate if exogenous addition of IL12/IL18 to PBMC cell cultures in the presence of M. leprae antigens could induce recovery of IFN-gamma levels. We found that IFN-gamma levels in PBMCs cultured from LL patients were reestablished after exogenous addition of exogenous IL12/IL18 and we also observed a diminished IL-18R expression. Although the molecular mechanisms of IL12/IL18 synergy have not been clearly elucidated, we assume that recombinant cytokines can activate several transcription factors that induce IFN-gamma synthesis.
Subject(s)
Interferon-gamma/drug effects , Leprosy, Lepromatous/immunology , Leukocytes, Mononuclear/drug effects , Adjuvants, Immunologic/pharmacology , Adult , Aged , Antigens, CD/drug effects , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/drug effects , Antigens, Differentiation, T-Lymphocyte/immunology , Antigens, Differentiation, T-Lymphocyte/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Drug Synergism , Female , Humans , Interferon-gamma/biosynthesis , Interleukin-12/pharmacology , Interleukin-18/pharmacology , Interleukin-18 Receptor alpha Subunit/drug effects , Interleukin-18 Receptor alpha Subunit/immunology , Interleukin-18 Receptor alpha Subunit/metabolism , Lectins, C-Type , Leprosy, Lepromatous/microbiology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/microbiology , Male , Middle Aged , Mitogens/pharmacology , Mycobacterium leprae/immunology , Phytohemagglutinins/pharmacology , Recombinant Proteins/pharmacologyABSTRACT
We examined the effect of IL-12 and IL-18 on bactericidal activities of mouse peritoneal cell (PC) against Mycobacterium leprae (M. leprae). We demonstrated that IL-12 and IL-18 synergistically induced the NO-dependent bactericidal activity of PC by stimulating Natural Killer (NK) cells and T-cells through IFN-gamma production. IL-12 and IL-18 induced host cell death through NK-cells and T-cells. Therefore. IL-12 and IL-18 play an important role on direct killing of intracellular M. leprae and on indirect killing of them through inducing host cell death.
Subject(s)
Interleukin-12/pharmacology , Interleukin-18/pharmacology , Mycobacterium leprae/immunology , Peritoneal Cavity/cytology , Animals , Cells, Cultured , Drug Synergism , Female , Interferon-gamma/metabolism , Interleukin-12/physiology , Interleukin-18/physiology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Mice , Mice, Inbred BALB C , Nitric Oxide/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
We investigated the role of IL-18 in leprosy, a disease characterized by polar cytokine responses that correlate with clinical disease. In vivo, IL-18 mRNA expression was higher in lesions from resistant tuberculoid as compared with susceptible lepromatous patients, and, in vitro, monocytes produced IL-18 in response to Mycobacterium leprae. rIL-18 augmented M. leprae-induced IFN-gamma in tuberculoid patients, but not lepromatous patients, while IL-4 production was not induced by IL-18. Anti-IL-12 partially inhibited M. leprae-induced release of IFN-gamma in the presence of IL-18, suggesting a combined effect of IL-12 and IL-18 in promoting M. leprae-specific type 1 responses. IL-18 enhanced M. leprae-induced IFN-gamma production rapidly (24 h) by NK cells and in a more sustained manner (5 days) by T cells. Finally, IL-18 directly induced IFN-gamma production from mycobacteria-reactive T cell clones. These results suggest that IL-18 induces type 1 cytokine responses in the host defense against intracellular infection.