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A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: dependence on CD28 signaling and preferential inhibition of IL-10 production.
Cell Immunol. 1999 Mar 15; 192(2):87-95.CI

Abstract

Cytokine production upon T cell activation results from the integration of multiple signaling pathways from TCR/CD3 and from costimulatory molecules such as CD28. Among these pathways, the possible role of p38 mitogen activated protein kinase (MAPK) is the least understood. Here, we used a highly specific p38 MAPK inhibitor, the SB203580 compound, to examine the role of this enzyme in the induction of various cytokines in human T cells stimulated with anti-CD3 and anti-CD28 mAb together or in combination with PMA. Cytokine induction was monitored by ELISA and at the mRNA level. While SB203580 had little effect on IL-2 production and proliferation, it significantly reduced the production of several other cytokines. The secretion of IL-4, IL-5, IL-13, and TNF-alpha was inhibited by 20-50% with modes of T cell activation involving the CD28 pathway, whereas their mRNA expression was little affected. In contrast, IFN-gamma induction via CD28/PMA or CD3/CD28, but not CD3/PMA, was markedly diminished both at the protein and at the mRNA levels. Most interestingly, SB203580 also suppressed IL-10 secretion and mRNA induction via CD28-dependent activation by 75-85% (IC50 approximately 0.2 microM). Subset analysis suggested that this inhibition did not reflect a differential effect on T cell subsets. Therefore, p38 MAPK activity appears to contribute to cytokine production, mostly via CD28-dependent signaling. Moreover, IL-10 seems to rely more on this activity than other cytokines for its induction in T cells.

Authors+Show Affiliations

Department of Immunology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10087176

Citation

Koprak, S, et al. "A Specific Inhibitor of the P38 Mitogen Activated Protein Kinase Affects Differentially the Production of Various Cytokines By Activated Human T Cells: Dependence On CD28 Signaling and Preferential Inhibition of IL-10 Production." Cellular Immunology, vol. 192, no. 2, 1999, pp. 87-95.
Koprak S, Staruch MJ, Dumont FJ. A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: dependence on CD28 signaling and preferential inhibition of IL-10 production. Cell Immunol. 1999;192(2):87-95.
Koprak, S., Staruch, M. J., & Dumont, F. J. (1999). A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: dependence on CD28 signaling and preferential inhibition of IL-10 production. Cellular Immunology, 192(2), 87-95.
Koprak S, Staruch MJ, Dumont FJ. A Specific Inhibitor of the P38 Mitogen Activated Protein Kinase Affects Differentially the Production of Various Cytokines By Activated Human T Cells: Dependence On CD28 Signaling and Preferential Inhibition of IL-10 Production. Cell Immunol. 1999 Mar 15;192(2):87-95. PubMed PMID: 10087176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: dependence on CD28 signaling and preferential inhibition of IL-10 production. AU - Koprak,S, AU - Staruch,M J, AU - Dumont,F J, PY - 1999/3/24/pubmed PY - 1999/3/24/medline PY - 1999/3/24/entrez SP - 87 EP - 95 JF - Cellular immunology JO - Cell Immunol VL - 192 IS - 2 N2 - Cytokine production upon T cell activation results from the integration of multiple signaling pathways from TCR/CD3 and from costimulatory molecules such as CD28. Among these pathways, the possible role of p38 mitogen activated protein kinase (MAPK) is the least understood. Here, we used a highly specific p38 MAPK inhibitor, the SB203580 compound, to examine the role of this enzyme in the induction of various cytokines in human T cells stimulated with anti-CD3 and anti-CD28 mAb together or in combination with PMA. Cytokine induction was monitored by ELISA and at the mRNA level. While SB203580 had little effect on IL-2 production and proliferation, it significantly reduced the production of several other cytokines. The secretion of IL-4, IL-5, IL-13, and TNF-alpha was inhibited by 20-50% with modes of T cell activation involving the CD28 pathway, whereas their mRNA expression was little affected. In contrast, IFN-gamma induction via CD28/PMA or CD3/CD28, but not CD3/PMA, was markedly diminished both at the protein and at the mRNA levels. Most interestingly, SB203580 also suppressed IL-10 secretion and mRNA induction via CD28-dependent activation by 75-85% (IC50 approximately 0.2 microM). Subset analysis suggested that this inhibition did not reflect a differential effect on T cell subsets. Therefore, p38 MAPK activity appears to contribute to cytokine production, mostly via CD28-dependent signaling. Moreover, IL-10 seems to rely more on this activity than other cytokines for its induction in T cells. SN - 0008-8749 UR - https://www.unboundmedicine.com/medline/citation/10087176/A_specific_inhibitor_of_the_p38_mitogen_activated_protein_kinase_affects_differentially_the_production_of_various_cytokines_by_activated_human_T_cells:_dependence_on_CD28_signaling_and_preferential_inhibition_of_IL_10_production_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0008-8749(98)91448-4 DB - PRIME DP - Unbound Medicine ER -