We concluded that YAP may play an important role in the regulation of abnormal keratinocyte proliferation via an AREG-dependent pathway and that YAP could be a new target in the treatment of psoriasis.
Amphiregulin, an epidermal growth factor receptor ligand, has functions in normal epithelial proliferation and aberrant neoplastic cell growth and is proinflammatory (e.g., rheumatoid arthritis, fibrosis) and active in hyperproliferative cutaneous conditions including psoriasis and wound healing.
Taken together, these data indicate an important role for amphiregulin in psoriatic hyperplasia and suggest that inhibition of amphiregulin activity could be an efficacious therapeutic strategy for psoriasis.
Moreover, there is enhanced transmigration of human neutrophils through polarized epithelial cell monolayers of MDCK cells after administration of AR, but not transforming growth factor-alpha, further supporting a specific role for AR in the pathogenesis of psoriasis.
Collectively, the results implicate epidermal AR expression as a possible mediator of innate cutaneous immunity and epidermal proliferation and also as a potential trigger of both cutaneous psoriasis and psoriatic arthritis.
Our results reveal that AR exerts activity in the skin that is distinct from that of transgenic transforming growth factor-alpha or other cytokines, and induces skin pathology with striking similarities to psoriasis.
We conclude: (i) the mitogenic signaling pathway(s) regulating S6 kinase is activated in psoriatic lesions, thus accounting for increased S6 kinase activity in the absence of increased S6 kinase gene or protein expression; (ii) S6 kinase activation in lesional keratinocytes likely occurs in response to EGF receptor stimulation by TGF-alpha and/or amphiregulin, which are known to be elevated in psoriatic lesions; and (iii) keratinocyte as well as T-cell mitogenic signaling pathways are susceptible to inhibition by rapamycin, suggesting that rapamycin may be of therapeutic benefit in the treatment of psoriasis.