Transforming growth factor-β downregulates interleukin-2-induced phosphorylation of signal transducer and activator of transcription 5 in human renal cell carcinoma

Purpose: We investigated signal transducer and activator of transcription-5 (STAT5) activation status in renal cell carcinoma (RCC) and the role of transforming growth factor-β (TGF-β) in the process. Methods: Twenty normal and RCC tissues were obtained from radical nephrectomy specimens for the assessment of expressions of phosphorylated STAT5 (p-STAT5) and TGF-β₁ (Western blot) and for localization and assessment of their relationship (immunohistochemical and immunofluorescence stains). By using four RCC cell lines and four primary cultured cells, the effect of TGF-β₁ and/or interleukin-2 (IL-2) on the expressions of p-STAT5 were analyzed. Results: In RCC samples, expression of p-STAT5 was significantly reduced while expression of TGF-β was enhanced compared with normal kidney tissues (P < 0.001 and P = 0.003, respectively). P-STAT5 was observed almost exclusively in the nuclei of normal kidney tissues while TGF-β was identified in the cytoplasm of cells of both tissues reflecting the Western results. In both RCC cell lines and cells from primary cultures, treatment with TGF-β or antibody did not significantly alter STAT5 activation. However, TGF-β significantly suppressed IL-2-induced STAT5 activation, whereas anti-TGF-β antibodies enhanced IL-2-induced STAT5 further. Conclusions: STAT5 activation is suppressed in RCC compared with normal renal parenchyma. It may be attributed to the RCC-derived TGF-β which also interferes with IL-2-induced STAT5 pathway activation.