Direct activation of aryl hydrocarbon receptor by benzo[a]pyrene elicits T‐helper 2‐driven proinflammatory responses in a mouse model of allergic dermatitis. Issue 7 (12th February 2019)

• Record Type: Journal Article
• Authors: Tajima, Hitoshi; Tajiki‐Nishino, Risako; Watanabe, Yuko; Fukuyama, Tomoki
• Is Part Of: Journal of applied toxicology. Volume 39:Issue 7(2019)
• Page Start: 936
• Page End: 944
• Publication Date: 2019-02-12
• Subjects: allergic dermatitis -- aryl hydrocarbon receptor -- benzo[a]pyrene -- FICZ -- keratinocyte -- T cells; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.3782
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: The aryl hydrocarbon receptor (AhR) is a ligand‐dependent transcription factor that binds to various environmental chemicals and contributes to numerous toxicological effects. However, the direct effects of AhR on the development of allergic diseases are not fully understood. The main aim of this study was to elucidate the action of AhR in the development of cutaneous allergies. Initially, the potential for a direct relationship between AhR and the immune cells was investigated in vitro, using murine bone marrow‐derived dendritic cells, human epidermal keratinocytes, and the mixed leukocyte reaction assay. Benzo[ a ]pyrene (BaP) and 6‐formylindolo[3, 2‐ b ]carbazole were used as selective ligands for the AhR. Pretreatment with BaP and/or 6‐formylindolo[3, 2‐ b ]carbazole significantly induced cytokine release by activated keratinocytes and T‐cell proliferation, whereas interleukin‐12 production in bone marrow‐derived dendritic cells was reduced by AhR activation. To confirm the in vitro results, in vivo experiments were also performed in T‐helper (Th)2‐type hapten toluene‐2, 4‐diisocyanate‐ and Th1‐type hapten dinitrochlorobenzene‐induced mouse models of allergic dermatitis. Mice were orally administered BaP at 48, 24 and 4 hours before the final allergen challenge. In the Th2 model, ear‐swelling response and scratching behavior were promoted by BaP exposure, which supported the observed significant increases in local cytokine secretion. The infiltration of helper T cells, B cells and dendritic cells into the auricular lymph node was significantly enhanced by BaP administration, although Th1‐type immune responses were not influenced by AhR activation. Our findings demonstrate that AhR activation directly activates keratinocytes and T cells, which leads to the exacerbation of Th2‐type cutaneous allergy. Abstract : To examine the direct action of aryl hydrocarbon receptor (AhR) in the development of cutaneous allergies, selective ligands for AhR were applied in vitro assays and mouse models of allergic dermatitis. Pretreatment with AhR ligands significantly induced cytokine release by keratinocytes and T‐cell proliferation. In the T‐helper 2‐type mouse model, both inflammatory and pruritic responses were promoted by AhR activation. Our findings demonstrate that AhR activation directly leads to the exacerbation of T‐helper 2‐type cutaneous allergy.