Effect of obesity on pulmonary inflammation induced by acute ozone exposure: role of interleukin-6.
To determine the role of interleukin (IL)-6 in the increased ozone (O3)-induced inflammation and injury observed in obese vs. lean mice, lean wild-type and leptin-deficient obese (ob/ob) mice were injected with anti-IL-6 antibody (Ab) or isotype control Ab 24 h before exposure to either O3 (2 ppm for 3 h) or room air. Four or 24 h after O3 exposure, bronchoalveolar lavage (BAL) was performed, and the lungs were harvested for Western blotting. Anti-IL-6 Ab caused substantial reductions in O3-induced increases in BAL IL-6 in mice of both genotypes. Four hours following O3, ob/ob mice had increased BAL neutrophils compared with controls, and anti-IL-6-Ab virtually abolished this difference. At 24 h, O3-induced increases in BAL protein and BAL serum albumin were augmented in ob/ob vs. wild-type mice, and anti-IL-6 Ab ablated these obesity-related differences in epithelial barrier injury. O3 increased tyrosine phosphorylation of STAT-3 and STAT-1. There was no effect of obesity on STAT-3 phosphorylation, whereas obesity decreased STAT-1 expression, resulting in reduced STAT-1 phosphorylation. IL-6 neutralization did not alter STAT-3 or STAT-1 phosphorylation in ob/ob or wild-type mice. O3 increased BAL leukemia inhibitory factor (LIF) to a greater extent in obese than in lean mice, and LIF may account for effects on STAT phosphorylation. Our results suggest that IL-6 plays a complex role in pulmonary responses to O3, a role that differs between wild-type and ob/ob mice. Moreover, obesity-related differences in activation of STAT proteins may contribute to some of the differences in the response of obese vs. lean mice.
Lang
Jason E
JE
Molecular and Integrative Physiological Sciences Program, Dept. of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115-6021, USA.
Williams
Erin S
ES
Mizgerd
Joseph P
JP
Shore
Stephanie A
SA
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D005260:Female; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000276:immunology*; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced* / Q000150:complications / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D000906:Antibodies; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D010126:Ozone