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Deprecated: Implicit conversion from float 253.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Toxicol+Sci 2013 ; 135 (1): 119-28 Nephropedia Template TP
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Metal allergens induce nitric oxide production by mouse dermal fibroblasts via the hypoxia-inducible factor-2alpha-dependent pathway #MMPMID23788631
Kuroishi T; Bando K; Endo Y; Sugawara S
Toxicol Sci 2013[Sep]; 135 (1): 119-28 PMID23788631show ga
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)-1beta 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-1beta. 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-1beta but not with PAMPs. On the other hand, IL-1beta 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-1beta, or both. A specific inhibitor for hypoxia-inducible factor (HIF)-2alpha, but not HIF-1alpha, inhibited NO production. Another frequent metal allergen, cobalt, also induced iNOS expression and NO production by MDF via the HIF-2alpha-dependent pathway. The inhibitor for iNOS augmented ear swelling in Ni allergy mouse model. On the other hand, HIF-2alpha inhibitor attenuates allergic inflammation. These results indicate that metal allergens induce NO production in MDF via the HIF-2alpha-dependent pathway and IL-1beta augments NO production, which suggests that the NO induced by metal allergens plays a pathological role in metal allergies.