Exp Mol Med.  2004 Aug;36(4):372-379.

IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21WAF1 and IRF-1

• Yu SJ
• Kim HS
• Cho SW
• Sohn J

Abstract

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 p27KIP1 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 p21WAF1 and interferon regulatory factor (IRF)-1, and decreasing the cyclin dependent kinase (CDK) 2 activity. Up-regulation of p21WAF1 and IRF-1 expression is transcriptional, but independent of p53. The levels of p21WAF1 and IRF-1 proteins were enhanced as early as 1 h 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 p27KIP1 and p16INK4a, nor the phosphorylation level of pRb was changed. The importance of p21WAF1 and IRF-1 in the growth inhibition induced by IL-4 was confirmed by antisense oligonucleotide transfection. Both of p21WAF1 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 p21WAF1 and IRF-1 mediate the growth inhibitory effect of IL-4 in human RCC cells.

Keyword

IL-4; interferon regulatory factor-1; p21WAF1; renal cell carcinoma

MeSH Terms

CDC2-CDC28 Kinases/metabolism
Carcinoma, Renal Cell/genetics/*metabolism
Cell Cycle/drug effects
Cell Cycle Proteins/genetics/*metabolism
Cell Line, Tumor
Cell Proliferation/drug effects
DNA-Binding Proteins/genetics/*metabolism
Gene Expression/drug effects
Humans
Interleukin-4/*pharmacology
Kidney Neoplasms/genetics/*metabolism
Oligonucleotides, Antisense/genetics
Phosphoproteins/genetics/*metabolism
Research Support, Non-U.S. Gov't