Independent Regulation of Tyrosinase by the Hypopigmenting Cytokines TGF Beta1 and TNF Alpha and the Melanogenic Hormone Alpha-MSH in B16 Mouse Melanocytes

In B16 melanocytes, tyrosinase activity and melanin formation are upregulated by alpha-MSH and downregulated by TGF beta1 and TNF alpha. Since TGF beta1 or TNF alpha block the differentiation programs induced by throphic hormones in other cell types, we studied tyrosinase regulation by alpha-MSH in the presence of the hypopigmenting cytokines, as well as the effects of the cytokines on several aspects of alpha-MSH signaling. TGF beta1 and TNF alpha only slightly diminished MC1 receptor gene expression, and had no effect on the intracellular levels of cAMP, or on the alpha-MSH-dependent cAMP rise. The intracellular levels of tyrosinase mRNA, protein and enzymatic activities were also upregulated by alpha-MSH in cells pretreated with TGF beta1 or TNF alpha. Therefore the cytokines do not block the response to alpha-MSH. However, the cytokine-induced inhibition of tyrosinase gene expression, protein levels and the reduction of tyrosinase intracellular half-life also occurred in the presence of alpha-MSH, indicating that the hormone does not override TGF beta1 or TNF alpha inhibition. Thus, tyrosinase activity and the rate of melanin formation in B16 melanocytes might reflect simply the balance between alpha-MSH stimulation and TGF beta1 or TNF alpha inhibition, acting by independent mechanisms.