Potential role for 8-oxoguanine DNA glycosylase in regulating inflammation.
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 beta-cell mass coupled with lower levels of the chemokine MIP-1alpha and Th1 cytokines IL-12 and TNF-alpha. 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.
Mabley
Jon G
JG
School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK. jgmabley@hotmail.com
Pacher
Pál
P
Deb
Amitabha
A
Wallace
Rebecca
R
Elder
Rhoderick H
RH
Szabó
Csaba
C
D000818:Animals; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003877:Dermatitis, Contact / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004731:Endotoxins / Q000009:adverse effects / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D012772:Shock, Septic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin
D004731:Endotoxins; D013311:Streptozocin; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse