Substance P and IL-33 synergistically stimulate mast cells to release IL-1β and TNF-α implicated in psoriasis; inhibition by the flavonoid methoxyluteolin (THER2P.960)

Psoriasis is an autoimmune skin disease characterized by keratinocyte hyperproliferation and inflammation. The pathogenesis of psoriasis appears to involve interactions among keratinocytes, mast cells (MC) and cytokines. MC are immune cells that secrete various cytokines and chemokines including interleukin (IL)-1 family of cytokines (IL-1β, 18, 33), which can stimulate keratinocyte activation. IL-33 also augments activation of MC with further release of several mediators such as TNF-α, IL-6, and prostaglandin D2. Also, IL-33 has synergistic effect with a neuropeptide substance P (SP) on VEGF release in MC. Both IL-33 and SP are upregulated in psoriatic skin. Moreover, SP stimulates keratinocytes to secrete IL-1β. Our findings show that SP and IL-33 synergistically stimulate MC to produce and release IL-1β and TNF-α, pro-inflammatory mediators involved in psoriasis pathogenesis. The combination of SP and IL-33 also significantly up-regulates IL-1β and TNF-α gene expression. The natural flavonoid methoxyluteolin (Metlut) is a potent inhibitor of both keratinocyte and MC activation. Here we report that Metlut significantly inhibits IL-1β and TNF-α gene expression, production and release triggered by SP and IL-33 combination. Therefore, Metlut-based formulations could be a novel treatment for psoriasis.