cAMP regulates IL-10 production by normal human T lymphocytes at multiple levels: A potential role for MEF2 (Journal article)

Liopeta, K./ Boubali, S./ Virgilio, L./ Thyphronitis, G./ Mavrothalassitis, G./ Dimitracopoulos, G./ Paliogianni, F.

Signal transduction by the cAMP/cAMP-dependent protein kinase A (PKA) pathway is triggered through multiple receptors and is important for many processes in a variety of cells. In T cells, the engagement of the TCR-CD3 complex induces CAMP, a second messenger that controls immune response. IL-10, produced by a variety of lymphocyte subpopulations, is an important regulator of this response exerting a wide range of immunomodulatory actions. Elevation of cAMP has been shown to increase IL-10 production by monocytes. However, the mechanism of cAMP mediated regulation of IL-10 production by T lymphocytes remains unclear. In this study using normal peripheral T lymphocytes stimulated either through the TCR-CD3 complex or the TCR-CD3 and the CD28 molecule, we show that IL-10 is produced mainly by memory T lymphocytes after either way of stimulation and is drastically inhibited (70-90%) by CAMP elevating agents. cAMP mediated inhibition was reversed by the use of the specific PKA inhibitor Rp-8-Br-cAMP but not by the addition of exogenous rhIL-2, indicating that the inhibitory effect depends on PKA activation and is not secondary to IL-2 inhibition, Inhibition is taking place at both transcriptional and posttranscriptional level. Transfection of a luciferase reporter plasmid carrying the IL-10 promoter in T cells, revealed that TCR/CD28-induced activation was inhibited by 60% by cAMP elevation. The most sensitive part to cAMP mediated inhibition was a fragment of 135 bp Upstream of TATA box, which contains multiple binding sites for MEF-2. Overexpression of MEF-2 in the same cells increased IL-10 promoter activity by 2.5-fold. Stimulation through TCR/CD28 increased MEF-2 binding in its Corresponding binding sites which was inhibited by 80% in the presence of cAMP elevating agents. These results suggest that the inhibitory effect of cAMP on IL-10 production by normal peripheral T lymphocytes is cell type and stimulus specific, exerted on multiple levels and involves MEF2 transcription factor. (C) 2008 Elsevier Ltd. All rights reserved.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών και Τεχνολογιών. Τμήμα Βιολογικών Εφαρμογών και Τεχνολογιών
Keywords: camp,il-10,t lymphocytes,mef2,pka,myocyte-enhancer factor-2,protein-kinase-a,necrosis-factor-alpha,gene-expression,transcription factors,interleukin-10 promoter,cell-proliferation,muscle development,prostaglandin e-2,binding protein
ISSN: 0161-5890
Link: <Go to ISI>://000262810400005
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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