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Prostaglandin I₂ Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells¹

Weisong Zhou^2,*, Koichi Hashimoto, Kasia Goleniewska^*, Jamye F. O’Neal^*, Shaoquan Ji, Timothy S. Blackwell^*, Garret A. FitzGerald, Karine M. Egan, Mark W. Geraci^¶ and R. Stokes Peebles, Jr.^*

^* Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Microbiology, Fukushima Medical University, Fukushima, Japan; LINCO Research, St. Charles, MO 63304; Departments of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104; and ^¶ Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262

Signaling through the PGI₂ receptor (IP) has been shown to inhibit inflammatory responses in mouse models of respiratory syncytial viral infection and OVA-induced allergic responses. However, little is known about the cell types that mediate the anti-inflammatory function of PGI_2. In this study, we determined that PGI₂ analogs modulate dendritic cell (DC) cytokine production, maturation, and function. We report that PGI₂ analogs (iloprost, cicaprost, treprostinil) differentially modulate the response of murine bone marrow-derived DC (BMDC) to LPS in an IP-dependent manner. The PGI₂ analogs decreased BMDC production of proinflammatory cytokines (IL-12, TNF-, IL-1, IL-6) and chemokines (MIP-1, MCP-1) and increased the production of the anti-inflammatory cytokine IL-10 by BMDCs. The modulatory effect was associated with IP-dependent up-regulation of intracellular cAMP and down-regulation of NF-B activity. Iloprost and cicaprost also suppressed LPS-induced expression of CD86, CD40, and MHC class II molecules by BMDCs and inhibited the ability of BMDCs to stimulate Ag-specific CD4 T cell proliferation and production of IL-5 and IL-13. These findings suggest that PGI₂ signaling through the IP may exert anti-inflammatory effects by acting on DC.

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 the American Academy of Allergy, Asthma, and Immunology Interest Section Award, R01-AI-054660, R01-HL-069949, and P30 CA68485.

² Address correspondence and reprint requests to Dr. Weisong Zhou, Center for Lung Research, Vanderbilt University Medical Center, T1218, Medical Center North, Nashville, TN 37232-2650. E-mail address: weisong.zhou{at}vanderbilt.edu

³ Abbreviations used in this paper: RSV, respiratory syncytial virus; IP, the PGI₂ receptor; DC, dendritic cell; BM, bone marrow; BMDC, BM-derived DC; LTR, long terminal repeat; IBMX, 3-isobutyl-1-methylxanthine; IKK, IB kinase; cIKK2, constitutively active IKK 2; COX, cyclooxygenase; PKA, protein kinase A; CBP, CREB-binding protein.

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