transforming-growth-factor-beta and Hypopigmentation

Melanocytes are generally characterized by the basic ability of melanin synthesis and transfer to adjacent keratinocytes. This constitutes an individual skin phenotype and provides epidermal protection from various stimuli, such as ultraviolet irradiation, through a complex process called melanogenesis, which can be regulated by autocrine or paracrine factors. Recent evidence has revealed the paracrine effects of keratinocytes on melanogenesis by secreting cytokines, including α-melanocyte stimulating hormone and endothelin-1. In addition to keratinocytes, there are other types of cells in the skin, such as fibroblasts and immune cells, which are also actively involved in the regulation of melanocyte behaviour through the production of paracrine factors. In addition, extracellular matrix proteins, which are secreted mainly by skin-resident cells, not only play direct roles in regulating melanocyte morphology and functions but also provide structural support between the epidermis and dermis to control the distribution of various secreted cytokines from keratinocytes and/or fibroblasts, which are potentially involved in the regulation of melanogenesis. Moreover, understanding the origin of melanocytes (neural crest cells) and the presence of nerve endings in the epidermis can reveal the intimate contact between melanocytes and cutaneous specific nervous system proteins. Melanocytes are associated with all these networks with corresponding receptors expressed on the cell surface. In this review, we provide an overview of recent advances in determining the intimate relationships between melanocytes and their surrounding elements, which provide insights into the complex nature of the regulation of melanogenesis.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Cell Proliferation; Cytokines; Disease Models, Animal; Extracellular Matrix Proteins; Fibroblasts; Humans; Hypopigmentation; Keratinocytes; Melanins; Melanocytes; Mice; Paracrine Communication; Skin Pigmentation; Transforming Growth Factor beta

Topics: Biomarkers; Bone Marrow Transplantation; Cytokines; Graft vs Host Disease; Humans; Hypopigmentation; Immunocompromised Host; Interleukin-1; Interleukin-6; Nevus, Pigmented; Skin Neoplasms; Transforming Growth Factor beta; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Transforming growth factor-beta1 (TGFbeta1) downregulates tyrosinase in B16 melanoma cells by decreasing gene expression and the intracellular half-life of the enzyme, but does not block tyrosinase stimulation by alpha-melanocyte stimulating hormone (alphaMSH). In the presence of both agents, the enzymatic activity is intermediate between the one of cells treated with either agent alone. Here we show that TGFbeta1 equally inhibits the melanogenic activities of melan-a melanocytes and B16 melanoma cells, thus validating the B16 model. In both cell types, TGFbeta1 (10(-10) M, 48 h) inhibited to comparable levels tyrosine hydroxylation and melanin formation from L-tyrosine. Thus, the inhibitory effect is exerted mainly at the rate limiting step of the pathway. By means of quantitative image analysis techniques, we also studied the effects of TGFbeta1 and alphaMSH on melanosome number, volume density and maturation degree. alphaMSH (10(-7) M, 48 h) increased 7-fold melanosome volume density, whereas TGFbeta1 by itself had no significant effect. However, melanosomal volume density was intermediate in cells treated with both agents, as compared to control or alphaMSH-treated cells. Moreover, TGFbeta1 blocked the alphaMSH-elicited increase in the number of melanosomes. Control and alphaMSH-treated melanocytes contained more stage I+II premelanosomes and stage IV, fully melanized organelles than partially melanized stage III melanosomes. TGFbeta1 increased the percentage of stage III melanosomes. This trend was even more marked in cells treated with alphaMSH and TGFbeta1. The accumulation of incompletely melanized melanosomes is consistent with the inhibition of melanin formation activity by TGFbeta1 and with its hypopigmenting effect.

Topics: alpha-MSH; Animals; Cell Differentiation; Down-Regulation; Gene Expression Regulation, Neoplastic; Half-Life; Hypopigmentation; Image Processing, Computer-Assisted; Kinetics; Melanins; Melanocytes; Melanoma, Experimental; Melanosomes; Mice; Microscopy, Electron; Monophenol Monooxygenase; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured