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United States Department of Agriculture

Agricultural Research Service

Research Project: DIETARY MODULATION OF OBESITY-RELATED CANCER BY SELENIUM Title: 8-oxoguanine DNA glycosylase 1-deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice

Authors
item Li, Guo-Ping -
item Yuan, Kefei -
item Fox, John -
item Gaid, Madeline -
item Seeger, Drew -
item Weaver, Andrew -
item Breitwieser, Wayne -
item Bansal, Arvind -
item Zeng, Huawei
item Gao, Hongwei -
item Wu, Min -

Submitted to: Free Radicals in Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 12, 2011
Publication Date: January 5, 2012
Citation: Li, G., Yuan, K., Fox, J., Gaid, M., Seeger, D., Weaver, A., Breitwieser, W., Bansal, A.K., Zeng, H., Gao, H., Wu, M. 2012. 8-oxoguanine DNA glycosylase 1-deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice. Free Radicals in Biology and Medicine. 15;52(2):392-401.

Interpretive Summary: 8-oxoguanine-DNA glycosylase (OGG-1) is an enzyme involved in DNA repair. OGG-1 has a potential role in regulating inflammation but its function in modulating allergic diseases remains undefined. To investigate the role of OGG-1 in mediating allergic inflammation, we used OGG-1 knockout (KO) mice to determine the impact of OGG1-deficiency on allergic airway inflammation. OGG-1 KO mice and WT mice were sensitized and challenged by ovalbumin (OVA) or control. The lung tissues were assessed for general morphology and cellular infiltration. Cytokine levels, oxidative stress, and OGG-1 activity in lung tissue were determined. These findings indicate that OGG-1 acts as an immune regulator of allergic response. Thus, OGG-1-deficiency plays a negative regulatory role in allergen-induced airway inflammatory response, suggesting that OGG-1 may aggravate allergic inflammatory response. The information will be useful for scientists and health-care professionals who are interested in the prevention of allergic inflammation.

Technical Abstract: Background: 8-oxoguanine-DNA glycosylase (OGG-1) is an enzyme involved in DNA repair. OGG-1 has a potential role in regulating inflammation but its function in modulating allergic diseases remains undefined. Objectives: To investigate the role of OGG-1 in mediating allergic inflammation, we used OGG-1 knockout (KO) mice to determine the impact of OGG1-deficiency on allergic airway inflammation. Methods: OGG-1 KO mice and WT mice were sensitized and challenged by ovalbumin (OVA) or control. The lung tissues were assessed for general morphology and cellular infiltration. Cytokine levels, oxidative stress, and OGG-1 activity in lung tissue were determined. STAT1, STAT3, STAT6, and NF-'B were quantified by western blot and immunohistochemistry. MLE-12 cells were stimulated with house dust mite (HDM) extracts (an allergen causing asthmatic symptoms). Using siRNA to knockdown OGG-1 in epithelial cells, we determined the impact of OGG-1 on the production of reactive oxygen species (ROS), NF-'B and STAT6. Results: OGG-1 KO mice exhibited lower inflammatory cell infiltration and reduced oxidative stress in the lungs after ovalbumin (OVA)-challenge compared to WT mice. These phenotypes were associated with lowered production of Th1 cytokines (TNF-a, INF-', IL-2, and IL-12), Th2 cytokines (IL-4, IL-6, and IL-10) and IL-17 in lung tissues. OGG-1 KO mice also showed reduced STAT3 and STAT6 expression as well as reduced STAT1 and NF-'B phosphorylation by OVA-challenge. To further investigate the role of OGG-1 in lung epithelial cells, OGG-1 siRNA was introduced into cultured MLE-12 cells. Down-regulation of OGG-1 in lung epithelial cells exhibited lower ROS release, IL-4, IL-2, and IL-17 production, but higher INF-' production. In addition, STAT6 expression and NF-'B phosphorylation were decreased in HDM extract-treated OGG-1 knockdown epithelial cells. Conclusions: These novel findings indicate that OGG-1 acts as an immune regulator of allergic response. Thus, OGG-1-deficiency plays a negative regulatory role in allergen-induced airway inflammatory response, suggesting that OGG-1 may aggravate allergic inflammatory response.

Last Modified: 10/23/2014
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