Immunomodulatory effects of pharmacological elevation of cyclic AMP in T lymphocytes proceed via a protein kinase A independent mechanism

The role of the cAMP pathway as an immunomodulatory system has been an area of intensive research. Pharmacological elevation of the cAMP pathway inhib its T lymphocyte proliferation and production of Th1-type cytokines. The ef fects of cAMP are thought to be mediated via activation of the intracellula r receptor, protein kinase A (PKA). We investigated the inhibitory effects of cAMP elevation on human lymphocyte proliferation and function by utilisi ng a range of selective inhibitors of PKA. Elevation of cAMP activity by db cAMP, Sp-cAMPS and forskolin induced significant decreases of Con A stimula ted PBMC proliferation. Go-incubation with the selective PKA inhibitors HA1 004, KT5720 and Rp-cAMPS showed these antiproliferative effects to persist, despite measurable PKA activity being inhibited to that of untreated cells or less. IL-2 production was also inhibited by dbcAMP in the presence of H A1004 and Rp-cAMPS. It has been demonstrated that the inhibitory effects of pharmacological elevations in cAMP on human T cell proliferation and IL-2 production do not require PKA activity. These observations indicate that co ntrol of lymphocyte proliferation and functional status by cAMP proceeds th rough PKA-independent events. Identification of the underlying mechanisms b ehind these effects would increase our understanding of the cAMP cascade an d may provide a potentially novel target for immunomodulation. (C) 1999 Els evier Science B.V. All rights reserved.