title: Role of the adiponectin binding protein, T-cadherin (cdh13), in pulmonary responses to subacute ozone.
abstract: Adiponectin, an adipose derived hormone with pleiotropic functions, binds to several proteins, including T-cadherin. We have previously reported that adiponectin deficient (Adipo(-/-)) mice have increased IL-17A-dependent neutrophil accumulation in their lungs after subacute exposure to ozone (0.3 ppm for 72 hrs). The purpose of this study was to determine whether this anti-inflammatory effect of adiponectin required adiponectin binding to T-cadherin. Wildtype, Adipo(-/-) , T-cadherin deficient (T-cad(-/-) ), and bideficient (Adipo(-/-)/T-cad(-/-) ) mice were exposed to subacute ozone or air. Compared to wildtype mice, ozone-induced increases in pulmonary IL-17A mRNA expression were augmented in T-cad(-/-) and Adipo(-/-) mice. Compared to T-cad(-/-) mice, there was no further increase in IL-17A in Adipo(-/-)/T-cad(-/-) mice, indicating that adiponectin binding to T-cadherin is required for suppression of ozone-induced IL-17A expression. Similar results were obtained for pulmonary mRNA expression of saa3, an acute phase protein capable of inducing IL-17A expression. Comparison of lung histological sections across genotypes also indicated that adiponectin attenuation of ozone-induced inflammatory lesions at bronchiolar branch points required T-cadherin. BAL neutrophils and G-CSF were augmented in T-cad(-/-) mice and further augmented in Adipo(-/-)/T-cad(-/-) mice. Taken together with previous observations indicating that augmentation of these moieties in ozone exposed Adipo(-/-) mice is partially IL-17A dependent, the results indicate that effects of T-cadherin deficiency on BAL neutrophils and G-CSF are likely secondary to changes in IL-17A, but that adiponectin also acts via T-cadherin independent pathways. Our results indicate that T-cadherin is required for the ability of adiponectin to suppress some but not all aspects of ozone-induced pulmonary inflammation.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health (HSPH), Boston, Massachusetts, United States of America.
authors.forename: David I
authors.initials: DI
authors.lastname: Kasahara
authors.forename: Alison S
authors.initials: AS
authors.lastname: Williams
authors.forename: Leandro A
authors.initials: LA
authors.lastname: Benedito
authors.forename: Barbara
authors.initials: B
authors.lastname: Ranscht
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: Christopher
authors.initials: C
authors.lastname: Hug
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Shore
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010126:Ozone / Q000009:adverse effects*
chemical_list: D052242:Adiponectin; D015820:Cadherins; D018925:Chemokines; D016207:Cytokines; C099972:H-cadherin; D010126:Ozone