title: Cyclic AMP activates p38 mitogen-activated protein kinase in Th2 cells: phosphorylation of GATA-3 and stimulation of Th2 cytokine gene expression.
abstract: cAMP is an important second messenger with immunomodulatory properties. Elevation of intracellular cAMP in T cells, induced by agents such as IL-1alpha or PGs, inhibits T cell activation. In effector T cells, an increase in the level of intracellular cAMP inhibits cytokine production in Th1 cells but stimulates cytokine production in Th2 cells. Here we report that cAMP-induced effects in Th2 cells occur independently of the protein kinase A pathway, which is the major mediator of cAMP-induced signaling events in most cell types. Instead, cAMP stimulates activation of p38 mitogen-activated protein kinase in Th2 cells. This appears to be a Th2-selective event because cAMP barely increased p38 phosphorylation in Th1 cells. We show that in Th2 cells, cAMP promotes the production of both IL-5 and IL-13, which play distinct but critical roles in asthma pathogenesis. Our data also show that cAMP causes increased phosphorylation of the transcription factor GATA-3, which we have shown is a critical regulator of Th2 cytokine gene expression and, in turn, of airway inflammation in mice. Thus, Th2-specific GATA-3 expression and p38 mitogen-activated protein kinase activation together provide a molecular basis for the differential effects of cAMP in the two T helper cell subsets.
authors.affiliation: Department of Medicine, Pulmonary and Critical Care Section, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Chen
authors.forename: D H
authors.initials: DH
authors.lastname: Zhang
authors.forename: J M
authors.initials: JM
authors.lastname: LaPorte
authors.forename: A
authors.initials: A
authors.lastname: Ray
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018417:Th1 Cells / Q000201:enzymology; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007093:Imidazoles; D018793:Interleukin-13; D015848:Interleukin-5; D011725:Pyridines; D012333:RNA, Messenger; D015534:Trans-Activators; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580