title: Alveolar Epithelial Cell-Derived Prostaglandin E2 Serves as a Request Signal for Macrophage Secretion of Suppressor of Cytokine Signaling 3 during Innate Inflammation.
abstract: Preservation of gas exchange mandates that the pulmonary alveolar surface restrain unnecessarily harmful inflammatory responses to the many challenges to which it is exposed. These responses reflect the cross-talk between alveolar epithelial cells (AECs) and resident alveolar macrophages (AMs). We recently determined that AMs can secrete suppressor of cytokine signaling (SOCS) proteins within microparticles. Uptake of these SOCS-containing vesicles by epithelial cells inhibits cytokine-induced STAT activation. However, the ability of epithelial cells to direct AM release of SOCS-containing vesicles in response to inflammatory insults has not been studied. In this study, we report that SOCS3 protein was elevated in bronchoalveolar lavage fluid of both virus- and bacteria-infected mice, as well as in an in vivo LPS model of acute inflammation. In vitro studies revealed that AEC-conditioned medium (AEC-CM) enhanced AM SOCS3 secretion above basal levels. Increased amounts of PGE2 were present in AEC-CM after LPS challenge, and both pharmacologic inhibition of PGE2 synthesis in AECs and neutralization of PGE2 in AEC-CM implicated this prostanoid as the major AEC-derived factor mediating enhanced AM SOCS3 secretion. Moreover, pharmacologic blockade of PGE2 synthesis or genetic deletion of a PGE2 synthase similarly attenuated the increase in bronchoalveolar lavage fluid SOCS3 noted in lungs of mice challenged with LPS in vivo. These results demonstrate a novel tunable form of cross-talk in which AECs use PGE2 as a signal to request SOCS3 from AMs to dampen their endogenous inflammatory responses during infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Jennifer M
authors.identifier: 0000-0002-7724-6995
authors.initials: JM
authors.lastname: Speth
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Emilie
authors.initials: E
authors.lastname: Bourdonnay
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Loka Raghu Kumar
authors.identifier: 0000-0002-2780-7950
authors.initials: LR
authors.lastname: Penke
authors.affiliation: Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Peter
authors.identifier: 0000-0002-2559-7320
authors.initials: P
authors.lastname: Mancuso
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Bethany B
authors.identifier: 0000-0003-3051-745X
authors.initials: BB
authors.lastname: Moore
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and Division of Infectious Diseases, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Jason B
authors.identifier: 0000-0002-4768-4361
authors.initials: JB
authors.lastname: Weinberg
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; petersm@umich.edu.
authors.forename: Marc
authors.identifier: 0000-0002-9768-0262
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003470:Culture Media; D015232:Dinoprostone / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation; D008070:Lipopolysaccharides / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D000071876:Prostaglandin-E Synthases / Q000172:deficiency / Q000235:genetics; D051381:Rats; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000276:immunology / Q000378:metabolism*
chemical_list: D003470:Culture Media; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone