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

被引:32
作者
Bryce, PJ [1 ]
Dascombe, MJ [1 ]
Hutchinson, IV [1 ]
机构
[1] Univ Manchester, Sch Biol Sci, Manchester M13 9PL, Lancs, England
来源
IMMUNOPHARMACOLOGY | 1999年 / 41卷 / 02期
关键词
cyclic AMP; immunomodulation; PKA; T lymphocyte;
D O I
10.1016/S0162-3109(98)00060-5
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The role of the cAMP pathway as an immunomodulatory system has been an area of intensive research. Pharmacological elevation of the cAMP pathway inhibits T lymphocyte proliferation and production of Th1-type cytokines. The effects of cAMP are thought to be mediated via activation of the intracellular receptor, protein kinase A (PKA). We investigated the inhibitory effects of cAMP elevation on human lymphocyte proliferation and function by utilising a range of selective inhibitors of PKA. Elevation of cAMP activity by dbcAMP, Sp-cAMPS and forskolin induced significant decreases of Con A stimulated PBMC proliferation. Go-incubation with the selective PKA inhibitors HA1004, 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 HA1004 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 control of lymphocyte proliferation and functional status by cAMP proceeds through PKA-independent events. Identification of the underlying mechanisms behind these effects would increase our understanding of the cAMP cascade and may provide a potentially novel target for immunomodulation. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:139 / 146
页数:8
相关论文
共 42 条
[31]   UP-REGULATION OF MONOCYTIC IL-10 BY TUMOR-NECROSIS-FACTOR-ALPHA AND CAMP ELEVATING DRUGS [J].
PLATZER, C ;
MEISEL, C ;
VOGT, K ;
PLATZER, M ;
VOLK, HD .
INTERNATIONAL IMMUNOLOGY, 1995, 7 (04) :517-523
[32]   MACROPHAGE GROWTH ARREST BY CYCLIC-AMP DEFINES A DISTINCT CHECKPOINT IN THE MID-G(1) STAGE OF THE CELL-CYCLE AND OVERRIDES CONSTITUTIVE C-MYC EXPRESSION [J].
ROCK, CO ;
CLEVELAND, JL ;
JACKOWSKI, S .
MOLECULAR AND CELLULAR BIOLOGY, 1992, 12 (05) :2351-2358
[33]   PROSTAGLANDIN E(2) INHIBITS B-LYMPHOCYTE ACTIVATION BY A CAMP-DEPENDENT MECHANISM - PGE-INDUCIBLE REGULATORY PROTEINS [J].
ROPER, RL ;
LUDLOW, JW ;
PHIPPS, RP .
CELLULAR IMMUNOLOGY, 1994, 154 (02) :296-308
[34]  
SCHIEKHATTER R, 1994, NEUROSCIENCE, V62, P523
[35]  
SEAMON KB, 1981, J CYCLIC NUCL PROT, V7, P201
[36]   CYCLIC NUCLEOTIDE-METABOLISM DURING LYMPHOCYTE-TRANSFORMATION .1. ENZYMATIC MECHANISMS IN CHANGES IN CAMP AND CGMP CONCENTRATION IN BALB-C MICE [J].
SHENKER, BJ ;
GRAY, I .
CELLULAR IMMUNOLOGY, 1979, 43 (01) :11-22
[37]   Regulation of chloride channel trafficking by cyclic AMP via protein kinase A-independent pathway in A6 renal epithelial cells [J].
Shintani, Y ;
Marunaka, Y .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 223 (02) :234-239
[38]  
SKALHEGG BS, 1992, J BIOL CHEM, V267, P15707
[39]   PGE(2)-induced immunoregulation mediated by cytokine production from cultures of human peripheral T lymphocytes. [J].
Sottile, A ;
Venza, I ;
Venza, M ;
Valenti, A ;
Teti, D .
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY, 1996, 18 (01) :27-36
[40]  
Sugiyama H, 1997, J IMMUNOL, V158, P171