Sensitivity of IL-5 production to the cAMP-dependent pathway in human T cells is reduced by exogenous IL-2 in a phosphoinositide 3-kinase-dependent way.
The cAMP-dependent pathway plays an important role in the regulation of T cell-mediated immune responses by inhibition of T cell proliferation, activation and production of Th1-like cytokines. Depending on costimulatory signals and on the activation status of T cells, cAMP also regulates the production of Th2-like cytokines, yet the mechanism is not completely defined. We investigated the effect of costimulation with IL-2 on cAMP-mediated inhibition of IL-5 secretion and the signaling pathways involved in these effects in freshly isolated, alpha-CD3/alpha-CD28-stimulated human T lymphocytes. We demonstrate that IL-2 counteracts the cAMP-mediated inhibitory effects on IL-5 secretion by the modulation of phosphoinositide 3-kinase (PI3-K)-dependent signaling. Our results indicate that phosphorylation of cAMP-responsive element-binding protein (CREB) and the activity of the small GTPase Rap1 are unlikely involved in the protective effect of IL-2. Instead, the effect of IL-2 may be mediated by the PI3-K-dependent inactivation of the forkhead-related transcription factor FKHR-L1, down-regulation of p27(kip) and abrogation of the cAMP-mediated inhibition of activator protein (AP)-1 binding activity. Together, our results indicate that increased IL-2-dependent PI3-K signaling leads to impaired negative feedback control of the production of Th2-type cytokine IL-5 by the cAMP-dependent pathway.
Heijink
Irene H
IH
Department of Allergology, University Hospital Groningen, Groningen, The Netherlands.
Kauffman
Henk F
HF
Postma
Dirkje S
DS
de Monchy
Jan G R
JG
Vellenga
Edo
E
D018797:Cell Cycle Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015232:Dinoprostone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D007376:Interleukin-2; D015848:Interleukin-5; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins; D015232:Dinoprostone