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Hypoxia Inhibits TNF-α-induced TSLP Expression in Keratinocytes

Hypoxia Inhibits TNF-α-induced TSLP Expression in Keratinocytes

Naoyuki Tashiro, Ryosuke Segawa, Ryozo Tobita, Sanki Asakawa, Natsumi Mizuno, Masahiro Hiratsuka, Noriyasu Hirasawa

PLoS One. 2019 Nov 4;14(11):e0224705.

PMID: 31682627

Abstract:

The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O2), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl2, CoCl2, and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1422955314	HIF-2 Antagonist 2		1422955-31-4	Price
AP89464631	DMOG		89464-63-1	Price

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