UVB Induces HIF-1α-Dependent TSLP Expression via the JNK and ERK Pathways

Abstract

Thymic stromal lymphopoietin (TSLP) may have a key role in the initiation and maintenance of allergic inflammatory diseases, including atopic dermatitis. The present study revealed that UVB radiation exposure could induce TSLP expression in human keratinocytes and a human skin equivalent model. In addition, we investigated the regulatory mechanism of UVB-induced TSLP expression in keratinocytes. TSLP expression was upregulated by transfection with pcDNA3-hypoxia-inducible factor (HIF)-1α (P402A and P564A), which stably expresses HIF-1α protein. UVB-induced TSLP induction in keratinocytes was suppressed in the treatment of mitogen-activated protein kinase inhibitors or small interfering RNAs against HIF-1α. The results of chromatin immunoprecipitation assays indicate the direct involvement of HIF-1α in UVB-mediated TSLP induction. Taken together, these findings indicate that UVB exposure may increase TSLP expression through a HIF-1α-dependent mechanism via the c-JUN N-terminal kinase and extracellular signal-regulated kinase pathways in human keratinocytes. Our data showed that UVB-induced TSLP might increase secretion of the T-helper type 2-attracting chemokine (c-c motif) ligand 17 by human dendritic cells. The present study suggests an important role of HIF-1α in UVB-mediated immune response in keratinocytes.

Dexamethasone but not tacrolimus suppresses TNF-α-induced thymic stromal lymphopoietin expression in lesional keratinocytes of atopic dermatitis model

“…Recent studies have revealed that TSLP expression is induced by TNF-a, synthetic double-stranded RNA poly (I:C), FSL-1, flagellin, kallikrein 5, and UVB in epidermal keratinocytes [6,21,31,32]. In AD, TNF-a is released by infiltrating mast cells, T-helper lymphocytes and epidermal keratinocytes [33].…”

Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis

“…17 IECs release TSLP that conditions mucosal DCs to noninflammatory tolerogenic DCs. Jang et al 49 demonstrated that the expression of TSLP in keratinocytes is HIF-1a dependent. We were unable to detect differences in the expression of TSLP in colon tissue probably because IECs in our model express active HIF-1a.…”

1α,25-Dihydroxyvitamin D3 upregulates HIF-1 and TREM-1 via mTOR signaling

“…3D). To verify the exact role of HIF-1␣ in TREM-1 expression, we used pcDNA3-HIF-1␣, which stably expresses HIF-1␣ protein by amino acid replacement on the hydroxylation site (P402A and P564A) [15]. The expression of HIF-1␣ was increased by pcDNA3-HIF-1␣ transfection at the mRNA and protein levels in PMA-differentiated U937 cells (Fig.…”

“…pcDNA3-HIF-1␣ was generated, as previously described [15]. PMA-differentiated U937 cells were transfected with either pcDNA3 empty vector or pcDNA3-HIF-1 using Lipofectamine (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions.…”