Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression

Maria Cecilia Rodriguez-Galán, Jay Bream, Andrew Farr, Howard A. Young

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2796-2804
Number of pages9
JournalJournal of Immunology
Volume174
Issue number5
StatePublished - Mar 1 2005
Externally publishedYes

Fingerprint

Interleukin-18
Thymocytes
Interleukin-12
Interleukin-2
Apoptosis
Cytokines
Interleukin-13
Thymus Gland
Interleukin-5
Cell Death
Epithelial Cells

ASJC Scopus subject areas

  • Immunology

Cite this

Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression. / Rodriguez-Galán, Maria Cecilia; Bream, Jay; Farr, Andrew; Young, Howard A.

In: Journal of Immunology, Vol. 174, No. 5, 01.03.2005, p. 2796-2804.

Research output: Contribution to journalArticle

Rodriguez-Galán, Maria Cecilia ; Bream, Jay ; Farr, Andrew ; Young, Howard A. / Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression. In: Journal of Immunology. 2005 ; Vol. 174, No. 5. pp. 2796-2804.
@article{4d64da690581410c9f6bbb6645ab7b9c,
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-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.",
author = "Rodriguez-Gal{\'a}n, {Maria Cecilia} and Jay Bream and Andrew Farr and Young, {Howard A.}",
year = "2005",
month = "3",
day = "1",
language = "English (US)",
volume = "174",
pages = "2796--2804",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=14044276321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14044276321&partnerID=8YFLogxK

M3 - Article

C2 - 15728489

AN - SCOPUS:14044276321

VL - 174

SP - 2796

EP - 2804

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -