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Transforming growth factor (TGF)-β1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-β1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-β1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-β1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-β1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-κB (NF-κB), JNK, and Ras. TGF-β1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by …