Menas Kizoulis

LIGR, a protease‐activated receptor‐2‐derived peptide, enhances skin pigmentation without inducing inflammatory processes

The protease‐activated receptor‐2 (PAR‐2) is a seven transmembrane G‐protein‐coupled receptor that could be activated by serine protease cleavage or by synthetic peptide agonists. We showed earlier that activation of PAR‐2 with Ser‐Leu‐Ile‐Gly‐Arg‐Leu‐NH2 (SLIGRL), a known PAR‐2 activating peptide, induces keratinocyte phagocytosis and increases skin pigmentation, indicating that PAR‐2 regulates pigmentation by controlling phagocytosis of melanosomes. Here, we show that Leu‐Ile‐Gly‐Arg‐NH2 (LIGR) can also induce skin pigmentation. Both SLIGRL and LIGR increased melanin deposition in vitro and in vivo, and visibly darkened human skins grafted onto severe combined immuno‐deficient (SCID) mice. Both SLIGRL and LIGR stimulated Rho‐GTP activation resulting in keratinocyte phagocytosis. Interestingly, LIGR activates only a subset of the PAR‐2 signaling pathways, and unlike SLIGRL, it does not induce inflammatory processes. LIGR did not affect many PAR‐2 signaling pathways, including [Ca2+] mobilization, cAMP induction, the induction of cyclooxgenase‐2 (COX‐2) expression and the secretion of prostaglandin E2, interleukin‐6 and ‐8. PAR‐2 siRNA inhibited LIGR‐induced phagocytosis, indicating that LIGR signals via PAR‐2. Our data suggest that LIGR is a more specific regulator of PAR‐2‐induced pigmentation relative to SLIGRL. Therefore, enhancing skin pigmentation by topical applications of LIGR may result in a desired tanned‐like skin color, without enhancing inflammatory processes, and without the need of UV exposure.

Inhibitory effect of topical applications of nondenatured soymilk on the formation and growth of UVB-induced skin tumors.

Treatment of female SKH-1 hairless mice with ultraviolet B light twice a week for 20 weeks resulted in a population of tumor-free mice with a high risk of developing skin tumors during the next several months in the absence of additional UVB treatment (high-risk mice). Topical applications of nondenatured soymilk but not heat-denatured soymilk once a day, 5 days a week to these high-risk mice inhibited the formation and growth of skin tumors. Similar topical applications of soybean trypsin inhibitor or Bowman-Birk inhibitor also inhibited the formation and growth of skin tumors, but these agents were less active than nondenatured soymilk. Treatment of miniswine skin with nondenatured soymilk once a day for 5 days prior to UVB irradiation reduced or completely eliminated UVB-induced formation of thymine dimers and apoptotic cells in the epidermis. These data suggest that nondenatured soymilk could be applied to humans to prevent sunlight-induced skin damage and to reduce the risk of skin tumor formation and progression.