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Published online before print November 29, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0606375

Received for publication June 6, 2006.
Revised October 23, 2006.
Accepted for publication October 30, 2006.

Article

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

Weisong Zhou ^*@, 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

^@ To whom correspondence should be addressed. E-mail: weisong.zhou{at}vanderbilt.edu.

	Abstract

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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