FK506 (tacrolimus) and endothelin combined treatment induces mobility of melanoblasts: new insights into follicular vitiligo repigmentation induced by topical tacrolimus on sun-exposed skin

P>Background Topical tacrolimus (FK506) has been considered as a treatment option for treating vitiligo, a dermatosis characterized by disappearance of melanocytes (MCs). Previous reports have shown that a significant portion of treated patients demonstrated follicular repigmentation, indicating that the activation of MC precursor cells residing in the outer root sheath of hair follicles played an important role during the tacrolimus-induced repigmentation process. Objectives To investigate the mechanisms involved in follicular pigmentation induced by topical tacrolimus. Methods As stem cells of MC lineage are identified in the lower portion of mouse hair follicles throughout the hair cycle, immature mouse melanoblasts (MBs) derived from neural crest cells (NCCmelb4) were used for this study. Relevant maturation parameters were evaluated. Results Our results revealed that FK506 stimulated the expressions of protein kinase A, protein kinase C and phosphorylated p38 mitogen-activated protein kinase. However, cell motility, a parameter associated with MB differentiation, was not enhanced by FK506 treatment. Endothelin (ET)-3, a prodifferentiation factor of MBs, also failed to promote NCCmelb4 cell locomotion. Combining ET-3 and FK506, however, stimulated cell mobility. ET B receptor, which was not present in NCCmelb4 cells, was induced after FK506 treatment. Conclusions In summary, we have shown that FK506 is an efficient differentiation-stimulating agent, especially for cells of neural origin. The clinical efficacy of topical tacrolimus on vitiligo may be enhanced by combination with ET-3.