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

Abstract

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, § -CD3/ § -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 cAMPresponsive 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.

Vasoactive Intestinal Peptide Induces Cell Cycle Arrest and Regulatory Functions in Human T Cells at Multiple Levels

“…The activation of the cAMP/PKA pathway seems to play a major role in all these VIP actions. Indeed, the effects of other cAMP/PKA-inducing agents in T-cell cycle arrest and p27 kip1 upregulation are well known (10,30,31,42,50,59).…”

Differential cAMP levels and serotonin effects in blood peripheral mononuclear cells and lymphocytes from major depression patients

“…It has been reported that cAMP inhibits macrophage suppressor function and increases spleen lymphocyte proliferation [16]. As indicated in the Introduction, the cAMP system exerts various actions in the immune system [5,19,33].…”

“…The cAMP-dependent pathway plays a significant role in regulating immune responses by inhibiting Tcell proliferation and increasing production of Th1-like cytokines [19]. Phosphorylation of the cAMPresponsive element-binding protein (CREB) plays a role in this process.…”

Differential Desensitization of Homozygous Haplotypes of the β2-Adrenergic Receptor in Lymphocytes

“…In contrast, no significant desensitization was observed for the ␤ 2 AR-mediated inhibition of IL-5 production. Both the relatively small inhibitory effect of (Ϫ)-isoproterenol on IL-5 production and the lack of desensitization of this effect might be related to the absence of a cAMP response element in the promoter sequence of the IL-5 gene (27,33). By contrast, the expression of IFN-␥ is under the control of a cAMP response element (34).…”