Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes

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.

An Increase in TNF-α Levels in Fetus due to Prenatal Ischemic Hypoxia

“…Furthermore, the results showed that the longer the prenatal hypoxia is, the higher the TNF value will be. It aligns with the previous research [19], [20], [21], revealing that hypoxia causes an increase in TNF [22], [23]. TNF-α is produced from various cells such as lymphoid cells, cardiac myocytes, activated macrophages, endothelial cells, mast cells, fibroblasts, neurons, and adipose tissue.…”

Role of Epithelium-Derived Cytokines in Atopic Dermatitis and Psoriasis: Evidence and Therapeutic Perspectives

“…This finding is unusual, considering that, at least some cytokines, appear to be more prominently represented in the acute phase of Pso rather than AD [ 34 ]., AD has been thoroughly studied in relation to both types of dermatoses, but Pso might represent an interesting field of study. In particular, the role of TNF-alpha should be evaluated, since TSLP appears to be conducive to an increase in TNF-alpha activity [ 35 , 37 ] and several molecules have been used so far to treat Pso by targeting TNF-alpha [ 63 ]. It is plausible to suggest that, since TNF-alpha treatments could lead to several side effects, including the development of new Pso lesions [ 64 ], targeting a molecule down the same pathway, in this case TSLP, could lead to better results in terms of skin clearance and less side effects.…”

“…Tashiro et al, using cultures of HaCaT cells (immortalized keratinocytes), found that TSLP, in hypoxic conditions, presents reduced levels via the inactivation of its production stimulated by TNF-alpha, via HIF2 and HRE mechanisms (two products involved in the skin response to hypoxemia). It is the authors’ suggestion that targeting these two molecules could lead to lower levels of TSLP and the resolution of lesions both in Pso and AD [ 37 ]. Schaper et al correlated the levels of TSLP from human skin samples derived from healthy controls, Pso patients and AD patients, noticing that both Pso and AD patients, but mostly Pso patients, presented higher levels of TSLP, especially the inflammation-related isoform rather than the basal one, via histamine release by hyper-active Th2 cells [ 34 ].…”

Immunological role of keratinocytes in leishmaniasis

“…HIF‐1α potentiates macrophage‐mediated immunity against L major and L amazonensis 89,90 . Hypoxia suppresses the expression of TSLP (a TH2 cell enhancer) in keratinocytes 91 . The wound healing is impaired in aged mice losing HIF‐1α in their keratinocytes 87 .…”