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Role of the adiponectin binding protein, T-cadherin (cdh13), in pulmonary responses to subacute ozone.

Kasahara DI, Williams AS, Benedito LA, Ranscht B, Kobzik L, Hug C, Shore SA - PLoS ONE (2013)

Bottom Line: Similar results were obtained for pulmonary mRNA expression of saa3, an acute phase protein capable of inducing IL-17A expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health, Harvard School of Public Health (HSPH), Boston, Massachusetts, United States of America.

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.

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Cytokine and chemokine expression.BAL IL-6 (A), G-CSF (B), LIF (C), IL-5 (D), pulmonary IL-17A mRNA expression (E), and soluble TNFR1 (sTNFR1) (F) in mice exposed to room air or O3 (0.3 ppm) for 72 hours. *p<0.05 versus air exposed mice of the same genotype, #p<0.05 versus wildtype mice with the same exposure, + p<0.05 versus T-cadherin deficient mice with the same exposure. Results are mean ± SEM of data from 3–5 air exposed mice and 3–7 ozone exposed mice for IL-6, G-CSF, LIF, and IL-5; 4–9 air exposed and 4–9 for ozone exposed mice for IL-17A mRNA; and 4–7 air exposed and 6–10 ozone exposed mice for sTNFR1;.
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pone-0065829-g003: Cytokine and chemokine expression.BAL IL-6 (A), G-CSF (B), LIF (C), IL-5 (D), pulmonary IL-17A mRNA expression (E), and soluble TNFR1 (sTNFR1) (F) in mice exposed to room air or O3 (0.3 ppm) for 72 hours. *p<0.05 versus air exposed mice of the same genotype, #p<0.05 versus wildtype mice with the same exposure, + p<0.05 versus T-cadherin deficient mice with the same exposure. Results are mean ± SEM of data from 3–5 air exposed mice and 3–7 ozone exposed mice for IL-6, G-CSF, LIF, and IL-5; 4–9 air exposed and 4–9 for ozone exposed mice for IL-17A mRNA; and 4–7 air exposed and 6–10 ozone exposed mice for sTNFR1;.

Mentions: To further evaluate the impact of T-cadherin deficiency on O3 induced inflammation, we performed a multiplex assay of cytokines and chemokines. Of the factors assayed by multiplex, factorial ANOVA indicated a significant effect of O3 exposure in both cohorts of mice (WT/Adipo−/− and WT/T-cad−/−/Adipo−/−/Tcad−/−) for G-CSF, IL-5, IL-6, LIF, KC, and eotaxin. BAL IL-6 and G-CSF were significantly higher in Adipo−/− versus WT mice exposed to O3 (Fig. 3A, B), consistent with our previous observations [8]. We also observed significantly higher BAL LIF and IL-5 in O3-exposed Adipo−/− versus WT mice (Fig. 3C, D). BAL G-CSF was also significantly higher in T-cad−/− versus WT mice exposed to O3, and higher still in Adipo−/−/T-cad−/− versus T-cad−/− mice (Fig. 3B). Surprisingly, O3-induced changes in BAL IL-5 were significantly reduced by T-cadherin deficiency, and this change was reversed by combined adiponectin and T-cadherin deficiency. Neither BAL IL-6 nor LIF was significantly affected by T-cadherin deficiency, although there was significantly greater BAL LIF in O3-exposed Adipo−/−/T-cad−/− versus WT mice and a similar trend for IL-6. There was no genotype effect for either eotaxin or KC (data not shown). IL-17A was below the limit of detection of the Bioplex assay, but IL-17A mRNA expression was induced by subacute O3 exposure. O3-induced increases in IL-17A were significantly greater in Adipo−/− than WT mice (Fig. 3E), consistent with our previous observations [8]. O3-induced increases in IL-17A were also significantly greater in T-cad−/− versus WT mice, and there was no further increase in Adipo−/−/T-cad−/− versus T-cad−/− mice.


Role of the adiponectin binding protein, T-cadherin (cdh13), in pulmonary responses to subacute ozone.

Kasahara DI, Williams AS, Benedito LA, Ranscht B, Kobzik L, Hug C, Shore SA - PLoS ONE (2013)

Cytokine and chemokine expression.BAL IL-6 (A), G-CSF (B), LIF (C), IL-5 (D), pulmonary IL-17A mRNA expression (E), and soluble TNFR1 (sTNFR1) (F) in mice exposed to room air or O3 (0.3 ppm) for 72 hours. *p<0.05 versus air exposed mice of the same genotype, #p<0.05 versus wildtype mice with the same exposure, + p<0.05 versus T-cadherin deficient mice with the same exposure. Results are mean ± SEM of data from 3–5 air exposed mice and 3–7 ozone exposed mice for IL-6, G-CSF, LIF, and IL-5; 4–9 air exposed and 4–9 for ozone exposed mice for IL-17A mRNA; and 4–7 air exposed and 6–10 ozone exposed mice for sTNFR1;.
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pone-0065829-g003: Cytokine and chemokine expression.BAL IL-6 (A), G-CSF (B), LIF (C), IL-5 (D), pulmonary IL-17A mRNA expression (E), and soluble TNFR1 (sTNFR1) (F) in mice exposed to room air or O3 (0.3 ppm) for 72 hours. *p<0.05 versus air exposed mice of the same genotype, #p<0.05 versus wildtype mice with the same exposure, + p<0.05 versus T-cadherin deficient mice with the same exposure. Results are mean ± SEM of data from 3–5 air exposed mice and 3–7 ozone exposed mice for IL-6, G-CSF, LIF, and IL-5; 4–9 air exposed and 4–9 for ozone exposed mice for IL-17A mRNA; and 4–7 air exposed and 6–10 ozone exposed mice for sTNFR1;.
Mentions: To further evaluate the impact of T-cadherin deficiency on O3 induced inflammation, we performed a multiplex assay of cytokines and chemokines. Of the factors assayed by multiplex, factorial ANOVA indicated a significant effect of O3 exposure in both cohorts of mice (WT/Adipo−/− and WT/T-cad−/−/Adipo−/−/Tcad−/−) for G-CSF, IL-5, IL-6, LIF, KC, and eotaxin. BAL IL-6 and G-CSF were significantly higher in Adipo−/− versus WT mice exposed to O3 (Fig. 3A, B), consistent with our previous observations [8]. We also observed significantly higher BAL LIF and IL-5 in O3-exposed Adipo−/− versus WT mice (Fig. 3C, D). BAL G-CSF was also significantly higher in T-cad−/− versus WT mice exposed to O3, and higher still in Adipo−/−/T-cad−/− versus T-cad−/− mice (Fig. 3B). Surprisingly, O3-induced changes in BAL IL-5 were significantly reduced by T-cadherin deficiency, and this change was reversed by combined adiponectin and T-cadherin deficiency. Neither BAL IL-6 nor LIF was significantly affected by T-cadherin deficiency, although there was significantly greater BAL LIF in O3-exposed Adipo−/−/T-cad−/− versus WT mice and a similar trend for IL-6. There was no genotype effect for either eotaxin or KC (data not shown). IL-17A was below the limit of detection of the Bioplex assay, but IL-17A mRNA expression was induced by subacute O3 exposure. O3-induced increases in IL-17A were significantly greater in Adipo−/− than WT mice (Fig. 3E), consistent with our previous observations [8]. O3-induced increases in IL-17A were also significantly greater in T-cad−/− versus WT mice, and there was no further increase in Adipo−/−/T-cad−/− versus T-cad−/− mice.

Bottom Line: Similar results were obtained for pulmonary mRNA expression of saa3, an acute phase protein capable of inducing IL-17A expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health, Harvard School of Public Health (HSPH), Boston, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus