Effects of 7,8-dihydro-8-oxo-deoxyguanosine on antigen challenge in ovalbumin-sensitized mice may be mediated by suppression of Rac.
OBJECTIVE
Earlier we reported that 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG), an oxidatively modified guanine nucleoside, exerted anti-inflammatory activity through inactivation of the GTP binding protein, Rac. In the present study, the effects of 8-oxo-dG were investigated on responses to antigen challenge in sensitized mice, as Rac is also involved at several steps of the immune process including antigen-induced release of mediators from mast cells.


METHODS
Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG during the challenge. Effects of 8-oxo-dG were assessed by measuring lung function, cells and cytokines in broncho-alveolar lavage fluid (BALF) and serum levels of antigen-specific IgE. Rac activity in BALF cells was also measured.


RESULTS
8-oxo-dG inhibited the increased airway resistance and decreased lung compliance of sensitized and challenged mice to the levels of non-sensitized control mice and lowered the increased leukocytes particularly, eosinophils, in BALF. Furthermore, 8-oxo-dG suppressed allergy-associated immune responses, such as raised anti- ovalbumin IgE antibody in serum, increased expression of CD40 and CD40 ligand in lung, increased interleukin-4, -5, -13, interferon-gamma and tumour necrosis factor-alpha in BALF and mRNA levels of these cytokines in BALF cells, dose-dependently. The corresponding purine, 8-oxo-guanine, showed no effects in the same experiments. Finally, 8-oxo-dG, but not 8-oxo-guanine, inhibited the increased Rac activity in sensitized and challenged mice.


CONCLUSIONS
8-Oxo-dG had anti-allergic actions that might be mediated by Rac inactivation. This compound merits further evaluation of its therapeutic potential in allergic asthma.
Ro
J Y
JY
Department of Pharmacology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
Kim
D Y
DY
Lee
S-H
SH
Park
J W
JW
Chung
M-H
MH
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003849:Deoxyguanosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D012129:Respiratory Function Tests; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D018926:Anti-Allergic Agents; D016207:Cytokines; D007073:Immunoglobulin E; C024829:8-hydroxyguanine; D006147:Guanine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D010047:Ovalbumin; D020744:rac GTP-Binding Proteins; D003849:Deoxyguanosine