The in vitro expression level of interleukin-8 (IL-8) correlates with the metastatic potential of human melanoma cells. The purpose of this study was to determine whether the expression level of IL-8 in human melanoma cells is influenced by the organ microenvironment. A375P cells, a low metastatic human melanoma, and A375SM cells, a highly metastatic variant, were injected into the subcutis (s.c.), spleen (to produce liver metastases), and lateral tail vein (to produce lung metastases) of athymic nude mice. Northern blot and immunohistochemical analyses determined that s.c. tumors, lung lesions, and liver lesions expressed high, intermediate, and low IL-8, mRNA, and protein, respectively. This differential regulation of IL-8 was not due to the size or density of the lesions or to selection of subpopulations of cells. We based this conclusion on the results of three experiments: (a) melanoma cell lines established in culture from in vivo-growing tumors exhibited similar levels of IL-8 mRNA transcripts; (b) in a crossover experiment, the level of IL-8 mRNA was always high in A375 tumors reestablished in the skin and low in the tumors reestablished in the liver, regardless of whether the melanoma cells had been first harvested from s.c. or liver tumors; and (c) A375 melanoma cells cocultured with human keratinocytes produced high levels of IL-8 protein, whereas A375 cells cocultured with highly differentiated human hepatoma cells produced decreased levels. When A375P cells were then incubated with cytokines associated with keratinocytes (IL-1 and interferon beta) or hepatocytes (transforming growth factor alpha or beta), IL-1 enhanced the production of IL-8 protein, whereas TGF-beta decreased its production. These data show that IL-8 expression in melanoma cells is modulated by local host factors.