title: IL-17-producing T lymphocytes in lung tissue and in the bronchoalveolar space after exposure to endotoxin from Escherichia coli in vivo--effects of anti-inflammatory pharmacotherapy.
abstract: Interleukin (IL)-17 may play a critical role for the innate immune response in mammals. However, little is known about its production in T lymphocytes in comparison with other cells, in lung tissue and in the bronchoalveolar space in vivo. Even less is known about the effects of anti-inflammatory pharmacotherapy on this IL-17 production. In this study on mice we show that one single, intranasal exposure to endotoxin from Escherichia coli increases extracellular IL-17 protein in bronchoalveolar (BAL) samples during 3 days, and is accompanied by a local increase in neutrophils and other inflammatory cells. This endotoxin exposure also elevates IL-17 mRNA in lung tissue samples. Moreover, after endotoxin exposure, the absolute number of CD3-positive cells containing intracellular IL-17 protein is increased as well; from a moderate cell number in lung tissue samples and from virtually none in BAL samples; with the number in lung tissue exceeding that observed in BAL samples. Notably, we also demonstrate that among the cells that contain intracellular IL-17 protein after endotoxin exposure, the percentage of CD3-positive cells is similar to that of CD3-negative cells in lung tissue. In contrast, CD3-negative cells dominate among IL-17-containing cells in BAL samples. A high systemic dose of a glucocorticoid receptor agonist attenuates the endotoxin-induced increase in extracellular IL-17 protein in BAL samples, IL-17 mRNA in lung tissue samples, and in IL-17-containing CD3-positive cells in BAL and lung tissue samples. This is also true for the endotoxin-induced accumulation of neutrophils and other inflammatory BAL cells in vivo. A systemic dose of a calcineurin phosphatase inhibitor exerts a less complete and more selective effect on the endotoxin-induced increase in extracellular IL-17 protein and on neutrophils in BAL samples. In vitro, endotoxin also increases extracellular IL-17 protein in a co-culture of CD3-positive spleen cells and adherent mononuclear BAL cells; an increase that was inhibited by a glucocorticoid as well as by a calcineurin phosphatase inhibitor. In conclusion, endotoxin-induced IL-17 production and release from T lymphocytes originates from cells that reside in lung tissue and from cells that have been recruited to the bronchoalveolar space. In both compartments, there is also a substantial number of cells other than T lymphocytes that contain IL-17 after endotoxin exposure. The sustained IL-17 production from T lymphocytes and the associated neutrophil accumulation may be inhibited non-selectively through glucocorticoid receptor stimulation and more selectively through calcineurin phosphatase inhibition.
authors.affiliation: Department of Internal Medicine/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 11B, S-413 45 Gothenburg, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Prause
authors.forename: Apostolos
authors.initials: A
authors.lastname: Bossios
authors.forename: Elin
authors.initials: E
authors.lastname: Silverpil
authors.forename: Stefan
authors.initials: S
authors.lastname: Ivanov
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.forename: Margareta
authors.initials: M
authors.lastname: Sjöstrand
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Anders
authors.initials: A
authors.lastname: Lindén
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001980:Bronchi / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D017252:CD3 Complex / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020381:Interleukin-17 / Q000096:biosynthesis*; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D017252:CD3 Complex; D004731:Endotoxins; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D012333:RNA, Messenger; C044101:endotoxin, Escherichia coli; D003907:Dexamethasone; D016572:Cyclosporine