Ghrelin Represses Thymic Stromal Lymphopoietin Gene Expression through Activation of Glucocorticoid Receptor and Protein Kinase C Delta in Inflamed Skin Keratinocytes

Abstract

Ghrelin, a peptide hormone secreted from enteroendocrine cells of the gastrointestinal tract, has anti-inflammatory activity in skin diseases including dermatitis and psoriasis. However, the molecular mechanism underlying the beneficial effect of ghrelin on skin inflammation is not clear. In this study, we found that ghrelin alleviates atopic dermatitis (AD)-phenotypes through suppression of thymic stromal lymphopoietin (TSLP) gene activation. Knockdown or antagonist treatment of growth hormone secretagogue receptor 1a (GHSR1a), the receptor for ghrelin, suppressed ghrelin-induced alleviation of AD-like phenotypes and suppression of TSLP gene activation. We further found that ghrelin induces activation of glucocorticoid receptor (GR), leading to binding of GR with histone deacetylase 3 (HDAC3) and nuclear receptor corepressor (NCoR) corepressor to negative glucocorticoid response element (nGRE) on the TSLP gene promoter. In addition, ghrelin induced protein kinase C δ (PKCδ)-mediated phosphorylation of p300 at serine 89 (S89), which decreased acetylation and DNA binding activity of nuclear factor- κB (NF-κB) p65 to the TSLP gene promoter. Knockdown of PKCδ abolished ghrelin-induced suppression of TSLP gene activation. Our study suggests that ghrelin may help to reduce skin inflammation through GR and PKCδ-p300-NF-κB-mediated suppression of TSLP gene activation.

The Role of Alarmins in the Pathogenesis of Rheumatoid Arthritis, Osteoarthritis, and Psoriasis

“…The injection of antibodies against TSLP in psoriasis-like mouse models has resulted in the regression of psoriasis, reduced epidermal hyperplasia, decreased VEGF α expression, and the epidermal inhibition of STAT-5 phosphorylation [236]. One of the possible directions of therapeutic strategies is the suppression of TSLP gene activation by ghrelin, which acts through the activation of glucocorticoid receptors [237]. Tashiro et al, studying the effects of hypoxia on TSLP, found an inhibition of the TNF-α -induced expression of TSLP in human and mouse keratinocyte cell lines.…”

The Role of TSLP in Atopic Dermatitis: From Pathogenetic Molecule to Therapeutical Target

“…In vitro experiments demonstrated that the TSLP expression is significantly elevated in TNF- α -inflamed HaCaT [ 43 ] and ploy (I:C)-induced NHEK cells [ 44 ]. Recent studies hinted that keratinocyte-expressed TSLP is upregulated via TLR [ 45 ] and histamine 4 receptor [ 46 ] while negatively regulated through glucocorticoid receptor [ 47 ] and aryl hydrocarbon receptor [ 48 ]. Furthermore, Yoo et al engineered a kind of transgenic mice (K5-TLSP transgenic mice) that overexpress tetracycline-inducible TSLP in keratinocytes under the control of the keratin 5 promotor [ 49 ].…”