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* Center for Environmental Health Sciences, Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812; and
Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
PGI2 plays a key role in limiting Th2-mediated airway inflammation. In studies to investigate the mechanism underlying such regulation, we found that the PGI2 receptor, IP, is preferentially expressed by effector CD4+ Th2 cells, when compared with Th1 cells. Adoptive transfer of DO11.10 Th2 cells pretreated with PGI2 resulted in considerably attenuated pulmonary inflammation and airway hyperreactivity in BALB/c recipient mice in response to OVA inhalation. This suppression was independent of increased cAMP levels, because pretreatment of Th2 cells with dibutyryl cAMP before transfer had no effect on airway inflammation. Moreover, PGI2 pretreatment of Th2 cells suppressed the ability of the cells to infiltrate the lungs but not the spleen. In vitro studies showed that PGI2 did not affect IL-4 and IL-5 production or the level of IFN-
by the T cells. However, the prostanoid strongly inhibited CCL17-induced chemotaxis of CD4+ Th2 but not Th1 cells. The IP was implicated in this process since migration of wild-type Th2 cells in response to CCL17 was markedly reduced following treatment with PGI2, whereas IP-deficient Th2 cells were unaffected and migrated effectively. Collectively, these experiments suggest that PGI2, which is generated by endothelial cells during lung inflammatory response, serves to limit the influx of Th2 cells to the airways. Our results identify PGI2-IP as an important pathway for inhibiting allergic pulmonary inflammation by controlling recruitment of CD4+ Th2 cells into the inflammatory site.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from National Heart, Lung and Blood Institute, National Institutes of Health (R01-HL079189-01A1 to K.R.) and Centers of Biomedical Research Excellence (Grant P20RR017670).
2 Address correspondence and reprint requests to Dr. Kevan Roberts or Dr. Zeina Jaffar, Center for Environmental Health Sciences, Biomedical and Pharmaceutical Sciences, 285B Skaggs Building, University of Montana, Missoula, MT 59812. E-mail addresses: kevan.roberts{at}umontana.edu or zeina.jaffar{at}umontana.edu
3 Abbreviations used in this paper: AHR, airway hyperreactivity; Treg, regulatory T cell; COX, cyclooxygenase; BAL, bronchoalveolar lavage; dbcAMP, dibutyryl cAMP; EPO, eosinophil peroxidase; LMC, lung mononuclear cell; Penh, enhanced pause; PGI2, prostacyclin; PLN, peripheral lymph node cell; IP, PGI2 receptor; EIA, enzyme immunoassay; PPAR, peroxisome proliferator-activated receptor; Penh, enhanced pause.
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