Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells.
An anti-inflammatory effect of PGI(2) has been suggested by increased inflammation in mice that are deficient in the PGI(2) receptor (IP) or in respiratory syncytial viral- or OVA-induced CD4 T cell-associated responses. To determine the mechanism of the anti-inflammatory effect, we hypothesized that PGI(2) analogs inhibit CD4 T cell effector cytokine production. To test this hypothesis, we activated purified CD4 T cells with anti-CD3 and anti-CD28 antibodies under Th1 and Th2 polarizing conditions for 4 days and restimulated the T cells with anti-CD3 in the presence of PGI(2) analogs for 2 days. We found that PGI(2) analogs (cicaprost and iloprost) inhibited the production of Th1 cytokines (IFN-gamma) and Th2 cytokines (IL-4, IL-10, and IL-13) in a dose-dependent pattern. The inhibitory effect was partially dependent on the IP receptor signaling and was correlated with elevated intracellular cAMP and down-regulated NF-kappaB activity. Pretreatment of the CD4 T cells with 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer, to inhibit a key signaling molecule in the cAMP pathway, protein kinase A (PKA), attenuated the suppressive effect of PGI(2) analogs significantly, suggesting that PKA, in part, mediates the inhibition of the cytokine production. These data indicate that PGI(2) analogs have an immune-suppressive effect on previously activated and differentiated CD4 T cells in vitro and suggest that PGI(2) may have a similar function in vivo.
Zhou
Weisong
W
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2650, USA. weisong.zhou@vanderbilt.edu
Blackwell
Timothy S
TS
Goleniewska
Kasia
K
O'Neal
Jamye F
JF
Fitzgerald
Garret A
GA
Lucitt
Margaret
M
Breyer
Richard M
RM
Peebles
R Stokes
RS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology*; D016285:Iloprost / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
D016207:Cytokines; D016328:NF-kappa B; D011982:Receptors, Prostaglandin; D011464:Epoprostenol; D000242:Cyclic AMP; D016285:Iloprost; C043867:cicaprost