Activation of Aryl Hydrocarbon Receptor Negatively Regulates Thymic Stromal Lymphopoietin Gene Expression via Protein Kinase Cδ-p300–NF-κB Pathway in Keratinocytes under Inflammatory Conditions

Abstract

Epithelial-derived thymic stromal lymphopoietin (TSLP) plays an important role in pathogenesis in several types of dermatitis. Recently, the anti-inflammatory effects of aryl hydrocarbon receptor (AhR) have been reported in inflamed skin. In this study, keratinocytes were stimulated with tumor necrosis factorea or flagellin in combination with AhR ligands or antagonist. TSLP gene expression and recruitment of transcriptional regulator to TSLP gene promoter were determined. The effects of AhR activation were also studied in DNFB-induced dermatitis model. We found that AhR activation suppressed upregulation of TSLP expression in keratinocytes treated with tumor necrosis factorea or flagellin. In addition, AhR activation induced protein kinase Cdemediated phosphorylation of p300 at serine 89, leading to decreased acetylation and DNA binding activity of NF-kB p65 to the TSLP gene promoter. We also found that AhR activation alleviates dermatitis induced by DNFB treatment. Protein kinase Cd depletion by small interfering RNA abolished the beneficial effect of AhR activation on dermatitis. Our study suggests that AhR activation may help to reduce inflammation in the dermatitis via downregulation of TSLP expression.

Increased IL-26 Expression Promotes T Helper Type 17- and T Helper Type 2-Associated Cytokine Production by Keratinocytes in Atopic Dermatitis

“…Simultaneously, recombinant IL-26 protein (2 mg/ml; MyBioSource) in 100 ml of phosphate buffered saline was injected subcutaneously in IL-26-treated group, whereas 100 ml of phosphate buffered saline was injected in control group on each day. On day 11, the score of AD-like phenotype was measured according to the criteria described previously (Jeong et al, 2019). Briefly, scores of 0 (none), 1 (mild), 2 (moderate), and 3 (severe) were given for each of the four symptoms: (i) erythema/ hemorrhage, (ii) edema, (iii) excoriation/erosion, and (iv) scaling/dryness.…”

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation

“…Given that keratinocytes, a major cell type in epidermis, contribute to AD pathogenesis and that up-regulation of cytokines including TSLP, IL-10, IL-13, and IL-25 is dependent on NF-κB activation in keratinocytes [ 32 , 33 , 34 , 35 ], we next investigated whether CA-PH modulates the NF-κB signaling pathway in HaCaT keratinocytes. CA-PH significantly suppressed up-regulation of TSLP, IL-10, IL-13, and IL-25 expression in TNFα-treated HaCaT keratinocytes ( Figure 2 A).…”

Inhibiting SARS-CoV-2 infectionin vitroby suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

“…CC-BY-NC 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted March 4, 2021. ; https://doi.org/10.1101/2021.03.04.433658 doi: bioRxiv preprint activity of NF-κB (Jeong et al, 2019). Another is decreased expression of the AP-1 family member Junb, which was substantially upregulated in the inflamed skin of Ahr-deficient mice (Di Meglio et al, 2014).…”