title: Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression.
abstract: In the periphery, IL-18 synergistically induces the expression of the Th1 cytokine IFN-gamma in the presence of IL-12 and the Th2 cytokines IL-5 and IL-13 in the presence of IL-2. Although the expression of these cytokines has been described in the thymus, their role in thymic development and function remains uncertain. We report here that freshly isolated thymocytes from C57BL/6 and BALB/c mice stimulated in vitro with IL-2-plus-IL-18 or IL-12-plus-IL-18 produce large amounts of IFN-gamma and IL-13. Analysis of the thymic subsets, CD4(-)CD8(-) (DN), CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) revealed that IL-18 in combination with IL-2 or IL-12 induces IFN-gamma and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-gamma(+) cells than cells in the later stage of maturation. Additionally, IL-18 in combination with IL-2 induces CCR4 (Th2-associated) and CCR5 (Th1-associated) gene expression. In contrast, IL-18-plus-IL-12 specifically induced CCR5 expression. The IL-2-plus-IL-18 or IL-12-plus-IL-18 effect on IFN-gamma and IL-13 expression is dependent on Stat4 and NF-kappaB but independent of Stat6, T-bet, or NFAT. Furthermore, IL-12-plus-IL-18 induces significant thymocyte apoptosis when expressed in vivo or in vitro, and this effect is exacerbated in the absence of IFN-gamma. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN-gamma-dependent manner. Thus, the combination of IL-2, IL-12, and IL-18 can induce phenotypic and functional changes in thymocytes that may alter migration, differentiation, and cell death of immature T cells inside the thymus and potentially affect the Th1/Th2 bias in peripheral immune compartments.
authors.affiliation: Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Rodriguez-Galán
authors.forename: Jay H
authors.initials: JH
authors.lastname: Bream
authors.forename: Andrew
authors.initials: A
authors.lastname: Farr
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology; D018793:Interleukin-13 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C515355:Ccr4 protein, mouse; D016207:Cytokines; D004338:Drug Combinations; D018793:Interleukin-13; D020382:Interleukin-18; D007376:Interleukin-2; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018664:Interleukin-12; D007371:Interferon-gamma