{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:36:28Z","timestamp":1790516188099,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration\u2013approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.1501063","type":"journal-article","created":{"date-parts":[[2016,7,26]],"date-time":"2016-07-26T02:43:28Z","timestamp":1469501008000},"page":"1577-1586","source":"Crossref","is-referenced-by-count":37,"title":["Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation"],"prefix":"10.1093","volume":"197","author":[{"given":"Weisong","family":"Zhou","sequence":"first","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasia","family":"Goleniewska","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E","family":"Dulek","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4379-9118","authenticated-orcid":false,"given":"Shinji","family":"Toki","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn C","family":"Newcomb","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline Y","family":"Cephus","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingsheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R","family":"Boothby","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1429-7875","authenticated-orcid":false,"suffix":"Jr.","given":"R Stokes","family":"Peebles","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine , Nashville, TN 37232"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"2025030617475126200_r1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1084\/jem.187.6.939","article-title":"Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production","volume":"187","author":"Kuperman","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025030617475126200_r2","doi-asserted-by":"crossref","first-page":"5360","DOI":"10.4049\/jimmunol.181.8.5360","article-title":"Cyclooxygenase inhibition during allergic sensitization increases STAT6-independent primary and memory Th2 responses","volume":"181","author":"Zhou","year":"2008","journal-title":"J. Immunol."},{"key":"2025030617475126200_r3","doi-asserted-by":"crossref","first-page":"525","DOI":"10.4049\/jimmunol.174.1.525","article-title":"Cyclooxygenase inhibition augments allergic inflammation through CD4-dependent, STAT6-independent mechanisms","volume":"174","author":"Hashimoto","year":"2005","journal-title":"J. Immunol."},{"key":"2025030617475126200_r4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1164\/rccm.201010-1637OC","article-title":"Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation","volume":"184","author":"Li","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030617475126200_r5","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1164\/rccm.200211-1383OC","article-title":"Accentuated T helper type 2 airway response after allergen challenge in cyclooxygenase-1-\/- but not cyclooxygenase-2-\/- mice","volume":"167","author":"Carey","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030617475126200_r6","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1172\/JCI6890","article-title":"Allergic lung responses are increased in prostaglandin H synthase-deficient mice","volume":"104","author":"Gavett","year":"1999","journal-title":"J. Clin. Invest."},{"key":"2025030617475126200_r7","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.jaci.2014.06.004","article-title":"Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling","volume":"134","author":"Zhou","year":"2014","journal-title":"J. Allergy Clin. 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Immunol."},{"key":"2025030617475126200_r16","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1165\/rcmb.2003-0035OC","article-title":"Role of prostaglandin I2 in airway remodeling induced by repeated allergen challenge in mice","volume":"29","author":"Nagao","year":"2003","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030617475126200_r17","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/sj.bjp.0704872","article-title":"Augmentation of allergic inflammation in prostanoid IP receptor deficient mice","volume":"137","author":"Takahashi","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"2025030617475126200_r18","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1073\/pnas.91.9.3652","article-title":"Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant","volume":"91","author":"Carr","year":"1994","journal-title":"Proc. Natl. Acad. Sci. 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Immunol."},{"key":"2025030617475126200_r33","first-page":"155","article-title":"Identification of interleukin-2 in human peripheral blood eosinophils","volume":"87","author":"Levi-Schaffer","year":"1996","journal-title":"Immunology"},{"key":"2025030617475126200_r34","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1126\/science.276.5312.589","article-title":"Control of inflammation, cytokine expression, and germinal center formation by BCL-6","volume":"276","author":"Dent","year":"1997","journal-title":"Science"},{"key":"2025030617475126200_r35","doi-asserted-by":"crossref","first-page":"7565","DOI":"10.4049\/jimmunol.173.12.7565","article-title":"Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma","volume":"173","author":"Fulkerson","year":"2004","journal-title":"J. Immunol."},{"key":"2025030617475126200_r36","doi-asserted-by":"crossref","first-page":"7276","DOI":"10.4049\/jimmunol.166.12.7276","article-title":"Stat6 is necessary and sufficient for IL-4\u2019s role in Th2 differentiation and cell expansion","volume":"166","author":"Zhu","year":"2001","journal-title":"J. Immunol."},{"key":"2025030617475126200_r37","doi-asserted-by":"crossref","first-page":"e17766","DOI":"10.1371\/journal.pone.0017766","article-title":"An alternate STAT6-independent pathway promotes eosinophil influx into blood during allergic airway inflammation","volume":"6","author":"Wang","year":"2011","journal-title":"PLoS One"},{"key":"2025030617475126200_r38","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.4049\/jimmunol.174.6.3734","article-title":"Indispensable role of Stat5a in Stat6-independent Th2 cell differentiation and allergic airway inflammation","volume":"174","author":"Takatori","year":"2005","journal-title":"J. Immunol."},{"key":"2025030617475126200_r39","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1084\/jem.185.12.2171","article-title":"Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes","volume":"185","author":"Forssmann","year":"1997","journal-title":"J. Exp. Med."},{"key":"2025030617475126200_r40","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1126\/science.277.5334.2005","article-title":"Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells","volume":"277","author":"Sallusto","year":"1997","journal-title":"Science"},{"key":"2025030617475126200_r41","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1159\/000053694","article-title":"Expression of the chemokine receptor CCR3 on human mast cells","volume":"124","author":"de Paulis","year":"2001","journal-title":"Int. Arch. Allergy Immunol."},{"key":"2025030617475126200_r42","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.4049\/jimmunol.169.5.2712","article-title":"Eotaxin (CCL11) and eotaxin-2 (CCL24) induce recruitment of eosinophils, basophils, neutrophils, and macrophages as well as features of early- and late-phase allergic reactions following cutaneous injection in human atopic and nonatopic volunteers","volume":"169","author":"Menzies-Gow","year":"2002","journal-title":"J. Immunol."},{"key":"2025030617475126200_r43","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1084\/jem.191.2.265","article-title":"CC chemokine receptor (CCR)3\/eotaxin is followed by CCR4\/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo","volume":"191","author":"Lloyd","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025030617475126200_r44","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.3892\/etm.2016.3141","article-title":"CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response","volume":"11","author":"Chen","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"2025030617475126200_r45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00109-010-0694-2","article-title":"Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation","volume":"89","author":"Kuo","year":"2011","journal-title":"J. Mol. Med. (Berl)."},{"key":"2025030617475126200_r46","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/ni1188","article-title":"Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3","volume":"6","author":"Kunikata","year":"2005","journal-title":"Nat. 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