We have previously shown that a majority of human melanoma cell lines derived from early-stage lesions were growth inhibited by exogenous interleukin 6 (IL-6) in vitro, whereas cell lines from advanced-stage lesions were resistant to such IL-6-induced growth inhibition. Among the resistant melanoma cell lines, 50-60% constitutively produced IL-6, which appeared to function as a growth stimulator in vitro, based on the growth-suppressive effects of antisense oligonucleotides to the IL-6 gene. The present study was primarily aimed at evaluating whether endogenous IL-6 also functions in vivo as a growth modulator for IL-6-producing and -nonproducing melanoma cells. To do so, we first introduced an IL-6 expression vector into IL-6-nonproducing human melanoma cells using WM35, an early-stage (radial growth phase) cell line, the growth of which is normally inhibited by IL-6, and WM983A, an advanced-stage cell line, the growth of which in vitro is not affected by exogenous IL-6. None of the IL-6-producing transfectants showed a significant alteration in tumor growth in nude mice. Next, two IL-6-producing melanoma cell lines, both of which were derived from metastases, MeWo and WM9, and which are growth resistant to exogenously added IL-6, were transfected with an antisense IL-6 expression vector. Several transfectant clones manifested a constitutive decrease in IL-6 gene expression and protein production, and they also gave rise to much smaller tumors with slower growth rates and longer latency periods. However, these IL-6 antisense transfectants were not growth suppressed in in vitro cell cultures, relative to their respective parental controls. Taken together, the results demonstrate that endogenous IL-6 can indeed function as a growth stimulator for human cutaneous melanomas in vivo. This growth-stimulatory or survival mechanism remains to be clarified but may be paracrine rather than autocrine in nature.