title: Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice.
abstract: Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin-deficient (Adipo(-/-)) mice. The IL-17/granulocyte colony-stimulating factor (G-CSF) axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo(-/-) mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo(-/-)/IL-6(-/-)) and exposed them to ozone or air. In ozone-exposed mice, bronchoalveolar lavage (BAL) neutrophils, IL-6, and G-CSF, and pulmonary Il17a mRNA expression were greater in Adipo(-/-) vs. wild-type mice, but reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice. IL-17A(+) F4/80(+) cells and IL-17A(+) γδ T cells were also reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice exposed to ozone. Only BAL neutrophils were reduced in IL-6(-/-) vs. wild-type mice. In wild-type mice, IL-6 was expressed in Gr-1(+)F4/80(-)CD11c(-) cells, whereas in Adipo(-/-) mice F4/80(+)CD11c(+) cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo(-/-) vs. wild-type mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo(-/-) vs. wild-type mice but reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo(-/-) mice after ozone exposure and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A, and G-CSF.
authors.affiliation: Molecular and Integrative Physiological Sciences Program, Dept. of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. dkasahar@hsph.harvard.edu.
authors.forename: David I
authors.initials: DI
authors.lastname: Kasahara
authors.forename: Hye Y
authors.initials: HY
authors.lastname: Kim
authors.forename: Joel A
authors.initials: JA
authors.lastname: Mathews
authors.forename: Norah G
authors.initials: NG
authors.lastname: Verbout
authors.forename: Alison S
authors.initials: AS
authors.lastname: Williams
authors.forename: Allison P
authors.initials: AP
authors.lastname: Wurmbrand
authors.forename: Fernanda M C
authors.initials: FM
authors.lastname: Ninin
authors.forename: Felippe L
authors.initials: FL
authors.lastname: Neto
authors.forename: Leandro A P
authors.initials: LA
authors.lastname: Benedito
authors.forename: Christopher
authors.initials: C
authors.lastname: Hug
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Shore
mesh_terms: D052242:Adiponectin / Q000172:deficiency*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D018655:Lymphocyte Count; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D010083:Oxidants, Photochemical / Q000494:pharmacology; D010126:Ozone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D052242:Adiponectin; D020381:Interleukin-17; D015850:Interleukin-6; D010083:Oxidants, Photochemical; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; D016179:Granulocyte Colony-Stimulating Factor; D010126:Ozone
keywords: CCL20; IL-17A; macrophages; neutrophils; serum amyloid A3; γδ T cells