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

Irene H. Heijink, HF Kauffman, DS Postma, JGR de Monchy, E Vellenga*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

15 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)2206-2215
Aantal pagina's10
TijdschriftEuropean Journal of Immunology
Volume33
Nummer van het tijdschrift8
DOI's
StatusPublished - aug.-2003

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