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Published online before print November 29, 2006

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(Journal of Leukocyte Biology. 2007;81:809-817.)
© 2007 by Society for Leukocyte Biology

Prostaglandin I₂ analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells

Weisong Zhou^*,1, Timothy S. Blackwell^*, Kasia Goleniewska^*, Jamye F. O’Neal^*, Garret A. FitzGerald, Margaret Lucitt, Richard M. Breyer and R. Stokes Peebles, Jr.^*

Departments of
^* Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, and
Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; and
Department of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹ Correspondence: Center for Lung Research, T-1218 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2650, USA. E-mail: weisong.zhou{at}vanderbilt.edu

An anti-inflammatory effect of PGI₂ has been suggested by increased inflammation in mice that are deficient in the PGI₂ 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 PGI₂ 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 PGI₂ analogs for 2 days. We found that PGI₂ analogs (cicaprost and iloprost) inhibited the production of Th1 cytokines (IFN-) 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-B 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 PGI₂ analogs significantly, suggesting that PKA, in part, mediates the inhibition of the cytokine production. These data indicate that PGI₂ analogs have an immune-suppressive effect on previously activated and differentiated CD4 T cells in vitro and suggest that PGI₂ may have a similar function in vivo.

Key Words: prostanoids • cAMP • lymphocytes • mouse

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