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Potential role for 8‐oxoguanine DNA glycosylase in regulating inflammation
Author(s) -
Mabley Jon G.,
Pacher Pal,
Deb Amitabha,
Wallace Rebecca,
Elder Rhoderick H.,
Szabó Csaba
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2278fje
Subject(s) - inflammation , chemokine , medicine , endocrinology , oxidative stress , lipopolysaccharide , dna glycosylase , cytokine , chemistry , biology , dna damage , biochemistry , dna
OGG‐1 DNA glycosylase (OGG‐1) is an enzyme involved in DNA repair. It excises 7,8‐dihydro‐8‐oxoguanine, which is formed by oxidative damage of guanine. We have investigated the role of OGG‐1 in inflammation using three models of inflammation: endotoxic shock, diabetes, and contact hypersensitivity. We found that OGG‐1 −/− mice are resistant to endotoxin (lipopolysaccharide, LPS)‐induced organ dysfunction, neutrophil infiltration and oxidative stress, when compared with the response seen in wild‐type controls (OGG +/+ ). Furthermore, the deletion of the OGG‐1 gene was associated with decreased serum cytokine and chemokine levels and prolonged survival after LPS treatment. Type I diabetes was induced by multiple low‐dose streptozotocin treatment. OGG‐1 −/− mice were found to have significantly lower blood glucose levels and incidence of diabetes as compared with OGG‐1 +/+ mice. Biochemical analysis of the pancreas showed that OGG‐1 −/− mice had greater insulin content, indicative of a greater β‐cell mass coupled with lower levels of the chemokine MIP‐1α and Th1 cytokines IL‐12 and TNF‐α. Levels of protective Th2 cytokines, IL‐4 and IL‐10 were significantly higher in the pancreata of OGG‐1 −/− mice as compared with the levels measured in wild‐type mice. In the contact hypersensitivity induced by oxazolone, the OGG‐1 −/− mice showed reduced neutrophil accumulation, chemokine, and Th1 and Th2 cytokine levels in the ear tissue. The current studies unveil a role for OGG‐1 in the regulation of inflammation.