[[alternative]]IL-1β mediates anti-progression activities in renal cell carcinoma by inducing MCP-1

[[abstract]]Background: Inflammation has a pivotal role in the carcinogenesis of renal cell carcinoma (RCC). Interleukin-1beta (IL-1ß) is a major mediator of inflammatory responses, thus its roles in RCC attract attention. A pro-metastasis role of IL-1ß has been proposed by a previous in vitro study. We aimed to assess the connection between IL-1ß and clinical consequences of RCC patients. Methods: Blood samples, tumor and the adjacent non-tumor tissues were collected from 26 RCC patients with pathological information. Intratumoral expressions of pro-IL-1ß and IL-1ß, or MCP-1 were examined by western blotting or immunohistochemical staining. Levels of IL-1ß and MCP-1 in serum or culture media of RCC cells were analyzed by ELISA and cytometric beads array. In vitro malignancies of RCC cells were examined by soft-agar clonogenicity and Matrigel-coated trans-well invasiveness. Results: Neither intratumoral expression nor serum level of IL1ß was associated with RCC progression in our patient cohort, implying that IL-1ß may elicit multiple activities in RCC. Here, we showed that IL-1ß treatment inhibits in vitro cancerous properties of RCC cell lines. IL1ß induced the secretion of MCP-1 by RCC cells. Exogenous MCP-1 negatively regulated the proliferation and BrdU incorporation of RCC cells. Blockage of IL-1ß or MCP-1 activities with neutralizing antibodies significantly increased the invasiveness of IL-1ß-highly secreting RCC cells. Furthermore, neutralizing antibodies against MCP-1 attenuated the invasion inhibitory effect of exogenous IL-1ß. Immunohistochemical staining showed that aggressive RCC expressed downregulated intratumoral MCP-1 whereas the tumors with MCP-1 overexpression were less malignant. A public array database showed that lower MCP-1 expression (n = 152) is associated with more aggressive tumor stages (T≧III, M1, N1) compared to those with earlier stages (n = 132, P = 0.015). Conclusions: IL-1ß-induced intratumoral MCP-1 expression is a novel mechanism by which IL-1ß exerts anti-tumor activities in RCC. Our data add another layer of complexity to IL-1ß effect on cancer and suggest more clinical applicability of MCP-1 than IL-1ß in RCC