Abstract
Background: IL-33, one of the IL-1 superfamily cytokines, has been shown to be associated with pruritus and inflammation in atopic dermatitis (AD). Furthermore, IL-33 production derived from keratinocytes reportedly has a crucial role in the development of AD; however, the mechanism of IL-33 expression has not been fully understood. Methods: We analyzed IL-33 expression in normal human epidermal keratinocytes (NHEKs) treated with IL-4. Results: IL-4 induced the upregulation of IL-33 expression in NHEKs. Based on the findings 1) that ovo-like 1 (OVOL1), a susceptible gene of AD, upregulates filaggrin (FLG) and loricrin (LOR) expression in NHEKs and 2) that reduced expression of FLG and LOR leads to production of IL-1 superfamily cytokines, we examined the involvement of OVOL1 in IL-33 expression in NHEKs. Knockdown of OVOL1 induced upregulation of IL-33 expression. Moreover, because Glyteer, an activator of aryl hydrocarbon receptor (AHR), reportedly upregulates OVOL1 expression, we examined whether treatment with Glyteer inhibited IL-33 expression in NHEKs. Treatment with Glyteer inhibited IL-4-induced upregulation of IL-33 expression, which was canceled by knockdown of either AHR or OVOL1. Conclusions: Activation of the AHR-OVOL1 axis inhibits IL-4-induced IL-33 expression, which could be beneficial for the treatment of AD.
Highlights
Atopic dermatitis (AD) is characterized by pruritus, cutaneous inflammation, and dry skin with epidermal barrier dysfunction [1]
Based on our previous finding that the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, upregulates OVO-like 1 (OVOL1) expression [11,12,13], we examined whether the activation of AHR by Glyteer, a soybean tar that is utilized for AD treatment clinically in Japan [16,17], inhibited IL-4-induced IL-33 expression in normal human epidermal keratinocytes (NHEKs)
To investigate the regulatory mechanism of IL-33 expression induced by IL-4, a key cytokine in the pathogenesis of AD [1], we examined this expression in NHEKs treated with IL-4
Summary
Atopic dermatitis (AD) is characterized by pruritus, cutaneous inflammation, and dry skin with epidermal barrier dysfunction [1]. It has been reported that IL-33 expression is increased in the epidermis of patients with AD [5] and that IL-33 production derived from keratinocytes has an important role in the development of AD-like skin lesions in experimental murine models [6,7]. This suggests the benefits of revealing the regulatory mechanism of IL-33 expression in keratinocytes, which could enable the control of pruritus and cutaneous inflammation in AD. These findings suggest that activation of the AHR-OVOL1 axis exerts an inhibitory effect on IL-33 expression induced by IL-4, which contributes to attenuate pruritus and disease activity in AD
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