IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21WAF1 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 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 approximately 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 approximately 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.
Yu
Su-Jin
SJ
Department of Biochemistry, College of Medicine, Korea University, Seoul, 136-705, Korea.
Kim
Hyeon Soo
HS
Cho
Sung-Won
SW
Sohn
Jeongwon
J
D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D015847:Interleukin-4 / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D015847:Interleukin-4; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2