The eumelanin intermediate 5,6-dihydroxyindole-2-carboxylic acid is a messenger in the cross-talk among epidermal cells.
Interest in colorless intermediates of melanocyte metabolism has traditionally been related to their role as melanin precursors, though several lines of evidence scattered in the literature suggested that these compounds may exert an antioxidant and protective function per se unrelated to pigment synthesis. Herein, we disclose the remarkable protective and differentiating effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA), a diffusible dopachrome tautomerase (DCT)-dependent eumelanin intermediate, on primary cultures of human keratinocytes. At micromolar concentrations, DHICA induced: (a) time- and dose-dependent reduction of cell proliferation without concomitant toxicity; (b) enhanced expression of early (spinous keratins K1 and K10 and envelope protein involucrin) and late (loricrin and filaggrin) differentiation markers; (c) increased activities and expression of antioxidant enzymes; and (d) decreased cell damage and apoptosis following UVA exposure. The hitherto unrecognized role of DHICA as an antiproliferative, protective, and antiapoptotic endogenous cell messenger points to a reappraisal of the biological functions of melanocytes and DCT in skin homeostasis and photoprotection beyond the mere provision of melanin pigments, and provides, to our knowledge, a previously unreported possible explanation to the higher resistance of the dark-skinned eumelanic phenotypes to sunburn and skin cancer.
Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute (IRCCS), Rome, Italy.
Daniela
D
Kovacs
Enrica
E
Flori
Vittoria
V
Maresca
Monica
M
Ottaviani
Nicaela
N
Aspite
Maria Lucia
ML
Dell'Anna
Lucia
L
Panzella
Alessandra
A
Napolitano
Mauro
M
Picardo
Marco
M
d'Ischia
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D013997:Time Factors
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007211:Indoles; D007381:Intermediate Filament Proteins; D008543:Melanins; D008565:Membrane Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D011498:Protein Precursors; C064554:loricrin; C041877:eumelanin; C030692:5,6-dihydroxy-2-indolylcarboxylic acid; C032253:involucrin; D007633:Keratins