IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21^WAF1 and IRF-1

Interleukin (IL)-4 inhibits proliferation of several human cancer cell lines in vitro. Although IL-4 is known to regulate proliferation of lymphocytes by modulating p27^KIP1 expression, the mechanism involved in the IL-4-induced growth inhibition of nonhematopoietic cancer cells has not been fully elucidated. Previously, we reported that IL-4 suppressed proliferation of human renal cell carcinoma (RCC) cell lines in vitro. Here, we show that IL-4 inhibits cell cycle progression at the G1 phase in Caki-1 cells by increasing the expression of p21^WAF1 and interferon regulatory factor (IRF)-1, and decreasing the cyclin dependent kinase (CDK) 2 activity. Up-regulation of p21^WAF1 and IRF-1 expression is transcriptional, but independent of p53. The levels of p21^WAF1 and IRF-1 proteins were enhanced as early as 1 after IL-4 treatment. CDK2 activity started to decline at 4 h after IL-4 treatment, and by 24 h, was ∼50% of the control. Neither the protein expressions of p27^KIP1 and p16^INK4a, nor the phosphorylation level of pRb was changed. The importance of p21^WAF1 and IRF-1 in the growth inhibition induced by IL-4 was confirmed by antisense oligonucleotide transfection. Both of p21^WAF1 and IRF-1 antisense oligonucleotides prevented IL-4-mediated growth inhibition by ∼30% compared to the respective sense oligonucleotides. In summary, our study indicated that p21^WAF1 and IRF-1 mediate the growth inhibitory effect of IL-4 in human RCC cells.