Expression and function of peroxisome proliferator-activated receptors in human melanocytes.

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors that heterodimerize with the retinoic X receptor. Agonists of PPAR have been known to play an important role in cellular responses including proliferation and differentiation. The expression and function of PPARs have not been investigated in human melanocytes, although they have been widely demonstrated in keratinocytes of the skin. To investigate the expression of PPARs in human melanocytes and the effects of PPAR activators on melanocyte growth and melanogenesis. We used immunocytochemistry and Western blot analysis to determine whether PPARs are expressed in melanocytes. To investigate further expression of PPAR subtypes, reverse transcriptase-polymerase chain reaction analysis was performed using PPAR subtype-specific oligonucleotides. The cell proliferation was measured using the Coulter counter. The effects on pigmentation were investigated with measurement of melanin contents, tyrosinase activity and its expression. The mRNA of all three PPAR subtypes, PPAR-alpha, PPAR-beta/delta and PPAR-gamma, were expressed in melanocytes. Activators for PPAR-alpha (WY-14643) and PPAR-gamma (ciglitazone) inhibited proliferation of melanocytes in a dose-dependent manner, whereas bezafibrate, a preferential activator for PPAR-beta/delta, had no effect. This growth inhibition was accompanied by the morphological change of the melanocytes to an activated form with an increased number of dendrites and enlarged cell area compared with the control. The WY-14643 and ciglitazone also appeared to stimulate the melanin synthesis of melanocytes. This increase in pigmentation was due to stimulation of the tyrosinase activity without an increase in the expression of tyrosinase. PPARs are expressed in human melanocytes and PPAR-alpha and PPAR-gamma activators inhibit melanocyte growth and stimulate melanogenesis.