p38α Mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells

Peter H. Schafer, Scott A. Wadsworth, Liwen Wang, John Siekierka

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Abstract

T cell proliferation and cytokine production usually require stimulation via both the TCR/CD3 complex and the CD28 costimulatory receptor. Using purified human CD4+ peripheral blood T cells, we show that CD28 stimulation alone activates p38α mitogen-activated protein kinase (p38α). Cell proliferation induced by CD28 stimulation alone, a response attributed to CD4+CD45RO+ memory T cells, was blocked by the highly specific p38 inhibitors SB 203580 (IC50 = 10-80 nM) and RWJ 67657 (IC50 = 0.5-4 nM). In contrast, proliferation induced by anti-CD3 plus anti-CD28 mAbs was not blocked. Inhibitors of p38 also blocked CD4+ T cell production of IL-4 (SB 203580 IC50 = 20-100 nM), but not IL-2, in response to CD3 and CD28 stimulation. IL-5, TNF-α, and IFN-γ production were also inhibited, but to a lesser degree than IL-4. IL-4 production was attributed to CD4+CD45RO+ T cells, and its induction was suppressed by p38 inhibitors at the mRNA level. In polarized Th1 and Th2 cell lines, SB 203580 strongly inhibited IL-4 production by Th2 cells (IC50 = 10-80 nM), but only partially inhibited IFN-γ and IL-2 production by Th1 cells (<50% inhibition at 1 μM). In both Th1 and Th2 cells, CD28 signaling activated p38α and was required for cytokine production. These results show that p38α plays an important role in some, but not all, CD28-dependent cellular responses. Its preferential involvement in IL-4 production by CD4+CD45RO+ T cells and Th2 effector cells suggests that p38α may be important in the generation of Th2-type responses in humans.

Original languageEnglish
Pages (from-to)7110-7119
Number of pages10
JournalJournal of Immunology
Volume162
Issue number12
StatePublished - 15 Jun 1999

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Th2 Cells
p38 Mitogen-Activated Protein Kinases
Interleukin-4
T-Lymphocytes
Th1 Cells
Inhibitory Concentration 50
Interleukin-2
T-Cell Antigen Receptor-CD3 Complex
Cell Proliferation
Cytokines
Interleukin-5
Blood Cells
Cell Line
Messenger RNA
SB 203580

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@article{6db662f300d64f349a1fec567513cd3c,
title = "p38α Mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells",
abstract = "T cell proliferation and cytokine production usually require stimulation via both the TCR/CD3 complex and the CD28 costimulatory receptor. Using purified human CD4+ peripheral blood T cells, we show that CD28 stimulation alone activates p38α mitogen-activated protein kinase (p38α). Cell proliferation induced by CD28 stimulation alone, a response attributed to CD4+CD45RO+ memory T cells, was blocked by the highly specific p38 inhibitors SB 203580 (IC50 = 10-80 nM) and RWJ 67657 (IC50 = 0.5-4 nM). In contrast, proliferation induced by anti-CD3 plus anti-CD28 mAbs was not blocked. Inhibitors of p38 also blocked CD4+ T cell production of IL-4 (SB 203580 IC50 = 20-100 nM), but not IL-2, in response to CD3 and CD28 stimulation. IL-5, TNF-α, and IFN-γ production were also inhibited, but to a lesser degree than IL-4. IL-4 production was attributed to CD4+CD45RO+ T cells, and its induction was suppressed by p38 inhibitors at the mRNA level. In polarized Th1 and Th2 cell lines, SB 203580 strongly inhibited IL-4 production by Th2 cells (IC50 = 10-80 nM), but only partially inhibited IFN-γ and IL-2 production by Th1 cells (<50{\%} inhibition at 1 μM). In both Th1 and Th2 cells, CD28 signaling activated p38α and was required for cytokine production. These results show that p38α plays an important role in some, but not all, CD28-dependent cellular responses. Its preferential involvement in IL-4 production by CD4+CD45RO+ T cells and Th2 effector cells suggests that p38α may be important in the generation of Th2-type responses in humans.",
author = "Schafer, {Peter H.} and Wadsworth, {Scott A.} and Liwen Wang and John Siekierka",
year = "1999",
month = "6",
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pages = "7110--7119",
journal = "Journal of Immunology",
issn = "0022-1767",
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p38α Mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells. / Schafer, Peter H.; Wadsworth, Scott A.; Wang, Liwen; Siekierka, John.

In: Journal of Immunology, Vol. 162, No. 12, 15.06.1999, p. 7110-7119.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - p38α Mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells

AU - Schafer, Peter H.

AU - Wadsworth, Scott A.

AU - Wang, Liwen

AU - Siekierka, John

PY - 1999/6/15

Y1 - 1999/6/15

N2 - T cell proliferation and cytokine production usually require stimulation via both the TCR/CD3 complex and the CD28 costimulatory receptor. Using purified human CD4+ peripheral blood T cells, we show that CD28 stimulation alone activates p38α mitogen-activated protein kinase (p38α). Cell proliferation induced by CD28 stimulation alone, a response attributed to CD4+CD45RO+ memory T cells, was blocked by the highly specific p38 inhibitors SB 203580 (IC50 = 10-80 nM) and RWJ 67657 (IC50 = 0.5-4 nM). In contrast, proliferation induced by anti-CD3 plus anti-CD28 mAbs was not blocked. Inhibitors of p38 also blocked CD4+ T cell production of IL-4 (SB 203580 IC50 = 20-100 nM), but not IL-2, in response to CD3 and CD28 stimulation. IL-5, TNF-α, and IFN-γ production were also inhibited, but to a lesser degree than IL-4. IL-4 production was attributed to CD4+CD45RO+ T cells, and its induction was suppressed by p38 inhibitors at the mRNA level. In polarized Th1 and Th2 cell lines, SB 203580 strongly inhibited IL-4 production by Th2 cells (IC50 = 10-80 nM), but only partially inhibited IFN-γ and IL-2 production by Th1 cells (<50% inhibition at 1 μM). In both Th1 and Th2 cells, CD28 signaling activated p38α and was required for cytokine production. These results show that p38α plays an important role in some, but not all, CD28-dependent cellular responses. Its preferential involvement in IL-4 production by CD4+CD45RO+ T cells and Th2 effector cells suggests that p38α may be important in the generation of Th2-type responses in humans.

AB - T cell proliferation and cytokine production usually require stimulation via both the TCR/CD3 complex and the CD28 costimulatory receptor. Using purified human CD4+ peripheral blood T cells, we show that CD28 stimulation alone activates p38α mitogen-activated protein kinase (p38α). Cell proliferation induced by CD28 stimulation alone, a response attributed to CD4+CD45RO+ memory T cells, was blocked by the highly specific p38 inhibitors SB 203580 (IC50 = 10-80 nM) and RWJ 67657 (IC50 = 0.5-4 nM). In contrast, proliferation induced by anti-CD3 plus anti-CD28 mAbs was not blocked. Inhibitors of p38 also blocked CD4+ T cell production of IL-4 (SB 203580 IC50 = 20-100 nM), but not IL-2, in response to CD3 and CD28 stimulation. IL-5, TNF-α, and IFN-γ production were also inhibited, but to a lesser degree than IL-4. IL-4 production was attributed to CD4+CD45RO+ T cells, and its induction was suppressed by p38 inhibitors at the mRNA level. In polarized Th1 and Th2 cell lines, SB 203580 strongly inhibited IL-4 production by Th2 cells (IC50 = 10-80 nM), but only partially inhibited IFN-γ and IL-2 production by Th1 cells (<50% inhibition at 1 μM). In both Th1 and Th2 cells, CD28 signaling activated p38α and was required for cytokine production. These results show that p38α plays an important role in some, but not all, CD28-dependent cellular responses. Its preferential involvement in IL-4 production by CD4+CD45RO+ T cells and Th2 effector cells suggests that p38α may be important in the generation of Th2-type responses in humans.

UR - http://www.scopus.com/inward/record.url?scp=0033564341&partnerID=8YFLogxK

M3 - Article

VL - 162

SP - 7110

EP - 7119

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 12

ER -