Metal allergens induce nitric oxide production by mouse dermal fibroblasts via the hypoxia-inducible factor-2α-dependent pathway

Toshinobu Kuroishi, Kanan Bando, Yasuo Endo, Shunji Sugawara

研究成果: Article査読

14 被引用数 (Scopus)

抄録

Nickel (Ni) has been shown to be one of the most frequent metal allergens. We have already reported a murine metal allergy model with pathogen-associated molecular patterns (PAMPs) as adjuvants. Interleukin (IL)-1β plays a critical role in our mouse model. Because nonimmune cells, including fibroblasts, play important roles in local allergic inflammation, we investigated whether Ni induces inflammatory responses in mouse dermal fibroblasts (MDF). We also analyzed the synergistic effects between Ni, PAMPs, and IL-1β. MDF stimulated with Ni produced a significantly higher amount of nitric oxide (NO) in a dose-dependent manner. NO production was augmented by costimulation with IL-1β but not with PAMPs. On the other hand, IL-1β or PAMPs induced a significantly higher amount of IL-6 production by MDF, but no augmentation was detected in the presence of Ni. A specific inhibitor for inducible nitric oxide synthase (iNOS) inhibited Ni-induced NO production. iNOS mRNA expression was significantly higher in MDF stimulated with Ni, IL-1β, or both. A specific inhibitor for hypoxia-inducible factor (HIF)-2α, but not HIF-1α, inhibited NO production. Another frequent metal allergen, cobalt, also induced iNOS expression and NO production by MDF via the HIF-2α-dependent pathway. The inhibitor for iNOS augmented ear swelling in Ni allergy mouse model. On the other hand, HIF- 2α inhibitor attenuates allergic inflammation. These results indicate that metal allergens induce NO production in MDF via the HIF-2α-dependent pathway and IL-1β augments NO production, which suggests that the NO induced by metal allergens plays a pathological role in metal allergies.

本文言語English
ページ(範囲)119-128
ページ数10
ジャーナルToxicological Sciences
135
1
DOI
出版ステータスPublished - 2013 9

ASJC Scopus subject areas

  • 毒物学

フィンガープリント

「Metal allergens induce nitric oxide production by mouse dermal fibroblasts via the hypoxia-inducible factor-2α-dependent pathway」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル