TY - JOUR
T1 - Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression
AU - Rodriguez-Galán, Maria Cecilia
AU - Bream, Jay H.
AU - Farr, Andrew
AU - Young, Howard A.
PY - 2005/3/1
Y1 - 2005/3/1
N2 - In the periphery, IL-18 synergistically induces the expression of the TH1 cytokine IFN-γ 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-γ 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-γ and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-γ+ 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-γ and IL-13 expression is dependent on Stat4 and NF-κB 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-γ. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN-γ-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.
AB - In the periphery, IL-18 synergistically induces the expression of the TH1 cytokine IFN-γ 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-γ 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-γ and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-γ+ 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-γ and IL-13 expression is dependent on Stat4 and NF-κB 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-γ. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN-γ-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.
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U2 - 10.4049/jimmunol.174.5.2796
DO - 10.4049/jimmunol.174.5.2796
M3 - Article
C2 - 15728489
AN - SCOPUS:14044276321
SN - 0022-1767
VL - 174
SP - 2796
EP - 2804
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -