title: Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation.
abstract: 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-approved 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.
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and weisong.zhou@vanderbilt.edu.
authors.forename: Weisong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Dulek
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Shinji
authors.identifier: 0000-0003-4379-9118
authors.initials: S
authors.lastname: Toki
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Jacqueline Y
authors.initials: JY
authors.lastname: Cephus
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boothby
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: R Stokes
authors.identifier: 0000-0002-1429-7875
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001249:Asthma / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D049109:Cell Proliferation; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006967:Hypersensitivity; D007213:Indomethacin; D007249:Inflammation; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D044006:Receptors, Epoprostenol / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D000959:Antihypertensive Agents; D018925:Chemokines; D018793:Interleukin-13; D015848:Interleukin-5; D044006:Receptors, Epoprostenol; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D010047:Ovalbumin; D011464:Epoprostenol; C043867:cicaprost; D007213:Indomethacin