Independent regulation of tyrosinase by the hypopigmenting cytokines TGF beta 1 and TNF alpha and the melanogenic hormone alpha-MSH in B16 mouse melanocytes

In B16 melanocytes, tyrosinase activity and melanin formation are upregulat ed by alpha-MSH and downregulated by TGF beta 1 and TNF alpha. Since TGF be ta 1 or TNF alpha block the differentiation programs induced by throphic ho rmones in other cell types, we studied tyrosinase regulation by alpha-MSH i n the presence of the hypopigmenting cytokines, as well as the effects of t he cytokines on several aspects of a-MSH signaling. TGF beta 1 and TNF alph a only slightly diminished MC1 receptor gene expression, and had no effect on the intracellular levels of cAMP, or on the alpha-MSH-dependent cAMP ris e. The intracellular levels of tyrosinase mRNA, protein and enzymatic activ ities were also upregulated by alpha-MSH in cells pretreated with TGF beta 1 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 al so occurred in the presence of alpha-MSH, indicating that the hormone does not override TGF beta 1 or TNF alpha inhibition. Thus, tyrosinase activity and the rate of melanin formation in B16 melanocytes might reflect simply t he balance between alpha-MSH stimulation and TGF beta 1 or TNF alpha inhibi tion, acting by independent mechanisms.