Papel do metabolismo de triptofano e do interferon-γ na melanogênese

Abstract

Melanogenesis, a physiological process of skin pigmentation, is a defense mechanism in response to exposure to light and it is followed by rapid recruitment of immune cells. Both the pigmentation and the immune response are regulated by interferon-γ (IFN-γ). Among the many actions described for IFN-γ, it acts as the main inducer of indoleamine-2,3-dioxygenase (IDO), a key enzyme in tryptophan (Trp) metabolism. Considering also that some Trp metabolites have skin activity, the main objective of this work was to evaluate if the effect of IFN-γ on melanogenesis occurs through the modulation of Trp metabolism. In order to do this, we developed a model of melanogenesis induction in cultures of primary human skin cells, which relies on 1: 1 co-cultures of melanocytes and keratinocytes in the presence of 0.25 mM tyrosine and 5 mM NH4Cl. Using this model, quinurenine (KYN), which is a Trp metabolite, inhibits melanin production by reducing tyrosinase activity (TYR), similarly to that observed for IFN-γ. Additionally, when we treated this same model with 1-MT (known IDO inhibitor) we observed induction of melanin production. These data supported our hypothesis that the effect of IFN-γ on melanogenesis occurs through the modulation of Trp metabolism. Not only IFN-γ, which is an inducer of IDO, but also KYN (product of enzyme activity) causes a decrease in melanin concentration. In addition, when we added 1-MT, the melanin concentration was restored. KYN showed depigmenting activity not only in 2D co-cultures between melanocytes and keratinocytes, but also in reconstructed skin models in the laboratory, evidenced by the decrease of melanosomes observed in Fontana-Manson staining. These data, coupled with the possibility of incorporate KYN into two distinct formulations (gel, and nanoemulsion) suggest its topical use for skin whitening. The pigment action of 1-MT still deserves to be investigated, but it is also recognized as a possible active for topical use to treat hypochromic skin diseases. In this scenario, we are evaluating with the Agência USP de Inovação the existence of anterirorities and the innovative activity of the use of KYN and 1-MT in the preparation of a topical composition for whitening or pigmentation of the skin, respectively.