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p38 alpha 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.
J Immunol. 1999 Jun 15; 162(12):7110-9.JI

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 p38 alpha mitogen-activated protein kinase (p38 alpha). 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-alpha, and IFN-gamma 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-gamma and IL-2 production by Th1 cells (<50% inhibition at 1 microM). In both Th1 and Th2 cells, CD28 signaling activated p38 alpha and was required for cytokine production. These results show that p38 alpha 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 p38 alpha may be important in the generation of Th2-type responses in humans.

Authors+Show Affiliations

R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Research, Raritan, NJ 08869, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10358155

Citation

Schafer, P H., et al. "P38 Alpha 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." Journal of Immunology (Baltimore, Md. : 1950), vol. 162, no. 12, 1999, pp. 7110-9.
Schafer PH, Wadsworth SA, Wang L, et al. P38 alpha 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. J Immunol. 1999;162(12):7110-9.
Schafer, P. H., Wadsworth, S. A., Wang, L., & Siekierka, J. J. (1999). P38 alpha 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. Journal of Immunology (Baltimore, Md. : 1950), 162(12), 7110-9.
Schafer PH, et al. P38 Alpha 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. J Immunol. 1999 Jun 15;162(12):7110-9. PubMed PMID: 10358155.
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TY - JOUR T1 - p38 alpha 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,P H, AU - Wadsworth,S A, AU - Wang,L, AU - Siekierka,J J, PY - 1999/6/8/pubmed PY - 1999/6/8/medline PY - 1999/6/8/entrez SP - 7110 EP - 9 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 162 IS - 12 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 p38 alpha mitogen-activated protein kinase (p38 alpha). 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-alpha, and IFN-gamma 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-gamma and IL-2 production by Th1 cells (<50% inhibition at 1 microM). In both Th1 and Th2 cells, CD28 signaling activated p38 alpha and was required for cytokine production. These results show that p38 alpha 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 p38 alpha may be important in the generation of Th2-type responses in humans. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/10358155/p38_alpha_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_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&amp;pmid=10358155 DB - PRIME DP - Unbound Medicine ER -