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 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.
Highlights
IL-4, originally found as a B cell growth factor, possesses pleiotropic effects including Th2 cell differentiation, and class switching to IgE and IgG1
We investigated the mechanism of IL-4-induced growth inhibition in renal cell carcinom a (RCC) cells, and demonstrated that IL-4 increased the expression of p21WAF1 and interferon regulatory factor-1 (IRF-1) transcriptionally to induce growth suppression. p27KIP1, p16INK4a, and pRb were not involved in the IL-4-mediated growth inhibition in RCC cells
R e s u lts Effect of IL-4 on cell cycle progression Previously, we showed that IL-4 inhibited growth of all 3 human RCC cell lines, A498, CURCII and Caki-1
Summary
IL-4, originally found as a B cell growth factor, possesses pleiotropic effects including Th2 cell differentiation, and class switching to IgE and IgG1. P21WAF1/CIP1 is a member of the CIP/KIP family inhibitor of cyclin dependent kinases (CDKs) with a broad specificity It can arrest cell cycle pregression at both G1 and G2 phases (Deng et al, 1995; Medema et al, 1998). Whereas up-regulation of p21WAF1 in response to a genotoxic stress is mediated by p53, cellular accumulation of p21WAF1 upon TGF-β stimulation or during cellular differentiation and senescence is independent of p53 (Datto et al, 1995; Gartel et al, 1999; Eum et al, 2003) In both cases, the increase of p21WAF1 correlates with growth arrest, suggesting that it may be the common mediator for different growth inhibitory signals. IRF (interferon regulatory factor)-1 is a member of the IRF family transcription factors with a tumor suppressor activity It regulates cell cycle progression, apoptosis, and DNA repair. We investigated the mechanism of IL-4-induced growth inhibition in RCC cells, and demonstrated that IL-4 increased the expression of p21WAF1 and IRF-1 transcriptionally to induce growth suppression. p27KIP1, p16INK4a, and pRb were not involved in the IL-4-mediated growth inhibition in RCC cells
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