Introduction: Interleuin-6 (IL-6) is a physiologic cytokine produced by lymphatic cells. Growth of melanocytes and early stage melanoma can be inhibited, whereas metastatic melanoma cells are mostly resistant to the anti-proliferative effects of IL-6. It has been shown that nearly 50% of metastatic melanoma express IL-6 mRNA and secrete IL-6 into the supernatant.(1,2). These stage dependent effects are not fully understood yet.Statins induce apoptosis in melanoma cells. However, melanoma cells show different sensitivities to statins (3-5). Our aim was to investigate the effect of IL-6 in statin induced apoptosis of human melanoma cells.Methods: The secretion of IL-6 by metastatic melanoma cell lines (A375, 518A2) and cells that derived from an early lesion (WM 35) into the cell culture supernatant was investigated with ELISA. Furthermore we checked the activity of caspase 3 after statin treatment in the presence and absence of IL-6 or an IL-6 receptor blocking antibody (tocilizumab) by cleavage of specific fluorescent caspase substrates. Additionaly apoptosis was more closely investigated by using AnnexinV/PI staining. Phsophorylation of Stat3 and the regulation of pro- (Bax, Bak) and anti-apoptotic proteins (Bcl-2, Bxl-XL) was studied by western blot. Proliferation was measured with cell cycle analysis using PI staining.Results: Metastatic melanoma cells produce high amounts of IL-6 in contrast to WM 35. In addition they are highly sensitive to statin induced apoptosis with EC50 of 0,52μM (518A2) and 1,7μM according to caspase 3 activation. On the contrary WM 35 cells are much more resistant to statins with an calculated EC50 of 16μM . Interestingly IL-6 signalling is not disrupted in all cell lines as stimulation with IL-6 led to a strong phosphorylation of Stat-3.Coincubation of IL-6 led to an increase in the statin induced apoptosis of WM 35 cells. This effect was not seen in the metastatic counterparts. Statins can activate the intrinsic pathway of apoptosis which relies on the loss of mitochondrial membrane potential. We checked for the influence of IL-6 on the production of anti- and proapoptotic proteins of the Bcl-2 family. Interestingly the amount of the antiapoptotic protein Bcl-Xl was significantly decreased in WM 35 cells which may explain the increase in apoptosis upon IL-6 treatment. Blocking IL-6 signalling with tocilizumab had no effect on the proliferation of the melanoma cells. However a combined treatment of simvastatin and tocilizumab led to a decrease in caspase 3 activation in A375 and 518A2, compared to the treatment with simvastatin alone.Conclusion: Taken together our data prove the different sensitivities of melanoma cells to statin induced apoptosis. Moreover we clearly show that IL-6 facilitates apoptosis in early stage melanoma cells by the down-regulation of anti-apoptotic proteins.