Inhibition of interleukin-12 production in mouse macrophages by hydroquinone, a reactive metabolite of benzene, via suppression of nuclear factor-kappaB binding activity.
Exposure to cigarette smoke is known to increase the risk of the development of allergic disease associated with T helper type 2 (Th2)-mediated immune responses. IL-12 is known to suppress Th2 responses. In this study we investigated the effects of hydroquinone (HQ), a major metabolite of benzene present in large quantities in cigarette tar, on the production of IL-12 from mouse macrophages stimulated with lipopolysaccharide (LPS). HQ potently inhibited the LPS-induced IL-12 production in both primary mouse macrophages and RAW164.7 monocytic cells in a dose-dependent manner. The effect of HQ on IL-12 p40 promoter activation was analyzed by transfecting RAW264.7 monocytic cells with p40 promoter/luciferase constructs. The repressive effect mapped to a region in the p40 promoter containing a binding site for nuclear factor-kappaB (p40-kappaB). Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the kappaB site, which significantly decreased upon addition of HQ. Pre-incubation with HQ significantly prevented degradation of IkappaB protein in LPS-stimulated macrophage cells, indicating that HQ suppressed NF-kappaB binding activity by inhibiting the degradation of IkappaB protein. These findings suggest that HQ may, at least in part, enhance allergic immune responses by inhibiting the production of IL-12 in macrophages.
Kim
Eugene
E
College of Pharmacy and Research Institute of Drug Development, Biotechnology Research Institute, Chonnam National University, Gwangju 500-757, Republic of Korea.
Kang
Bok Yun
BY
Kim
Tae Sung
TS
D000818:Animals; D001554:Benzene / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006873:Hydroquinones / Q000378:metabolism* / Q000494:pharmacology*; D051550:I-kappa B Kinase; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D006873:Hydroquinones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018664:Interleukin-12; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D001554:Benzene; C031927:hydroquinone