TNF stimulates IL ‐6, CXCL 8 and VEGF secretion from human keratinocytes via activation of mTOR , inhibited by tetramethoxyluteolin

Psoriasis is an autoimmune skin disease characterized by keratinocyte hyperproliferation and chronic inflammation. The pathogenesis of psoriasis involves proinflammatory cytokines, such as tumor necrosis factor (TNF), but the mechanism of keratinocyte activation is not well understood. Here, we show thatTNF(10 or 50 ng/mL) stimulates a significant (P < .0001) gene expression and secretion of proinflammatoryIL‐6,CXCL8 andVEGFfrom both cultured human HaCaT and normal epidermal human keratinocytes (NHEKs). This effect occurs via activation of the mammalian target of rapamycin (mTOR) signalling complex as shown by Western blot analysis and phospho‐ELISAs. Pretreatment with the novel natural flavonoid tetramethoxyluteolin (10‐100 μmol L−1) significantly (P < .0001) inhibits gene expression and secretion (P < .0001) of all 3 mediators in a concentration‐dependent manner. Moreover, tetramethoxyluteolin (50 μmol L−1) appears to be a potent inhibitor of the phosphorylatedmTORsubstrates (pmTORSer2448, pp70S6KThr389and p4EBP1Thr37/46) as compared to knownmTORinhibitors in keratinocytes. The present findings indicate thatTNFstimulates skin inflammation viamTORsignalling. Inhibition by tetramethoxyluteolin may be used in the treatment for psoriasis.