Regular ArticleEXPRESSION OF IL-17 IN HUMAN MEMORY CD45RO+T LYMPHOCYTES AND ITS REGULATION BY PROTEIN KINASE A PATHWAY
Abstract
In the present study, the authors compared the interleukin 17 (IL-17 expression of human naive and phenotypically defined memory T cells as well as its regulation by cAMP pathway. Our data showed that IL-17 mRNA was highly expressed in memory human peripheral CD8+45RO+T cells and CD4+45RO+T cells when peripheral blood mononuclear cells were first stimulated with ionomycin/PMA. IL-17 expression in memory CD8+T cells required accessory signals since culture of ionomycin/PMA-activated CD8+45RO+T cells alone did not result to IL-17 expression. In contrast, memory CD4+T cell population seems to be more independent. IL-17 and interferon γ(IFN-γ) mRNA were both inhibited in the presence of PGE2or the cAMP analogue (dibutyryl-cAMP), while the anti-inflammatory cytokine IL-10 was highly increased. In contrast, naive CD45RA+T cells were unable to express IL-17 whatever the culture conditions. Naive CD4+and CD8+T cells were sensitive to the PKA regulatory pathway since they represent a significant source of IL-10 when PBMC were first cultured with ionomycin/PMA in the presence of either PGE2or db-cAMP. The authors showed that naive cells are highly dependent to their microenvironment, since culture of ionomycin/PMA-activated CD45RA+T cells alone did not result in detectable levels of cytokines even in the presence of PGE2. Results also showed that PGE2induced quite the same levels of intracellular cAMP in naive and memory cells suggesting that these cell populations are equally sensitive to PGE2. However, we suggest that PGE2may be more efficient in blocking both IL-17 and IFN-γ expression in already primed memory T cells, rather than in suppressing naive T cells that could represent a significant source of IL-10. Data suggest that PKA activation pathway plays a critical role in the regulation of cytokine profiles and consequently the functional properties of both human naive and memory CD4+and CD8+T cells during the immune and inflammatory processes.
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Interleukin 17 is a proinflammatory cytokine produced by CD4+ T cells when in the presence of a distinct set of cytokines and other cells. Preclinical and clinical studies have assigned a role to IL-17 in tissue inflammation and damage in patients with rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus. Antibodies blocking the action of IL-17 have already been approved to treat patients with psoriasis and it is expected that they may also benefit patients with other rheumatic diseases.
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Correspondence to: Naima Benbernou, Laboratory of Molecular Immunoregulation, National Institute of Health, NCI, Bldg 560, Room 31-56, Frederick Cancer Research and Development Center, MD 21702-1201, USA; E-mail:[email protected]