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- W2078398006 abstract "Background:IL-4 can directly inhibit growth of several tumor cell types, but the molecular mechanism is not known.Results: IL-4 induces senescence by increasing p21WAF1/CIP1 expression through STAT6 and p38 MAPK.Conclusion: STAT6 and p38 MAPK play important roles in senescence induction by IL-4.Significance: This is the first report of cellular senescence induction by IL-4 and the responsible mechanism.Interleukin (IL)-4, originally identified as a lymphocyte growth factor, can directly inhibit growth of certain tumor cell types. We reported previously that IL-4 induced cell cycle arrest in G1 phase through an increase in p21WAF1/CIP1 expression in human renal cell carcinoma (RCC) cell lines. In the present study, we investigated the underlying mechanism of IL-4-induced growth inhibition. In four of six human RCC cell lines, including Caki-1, A498, SNU482, and SNU228, IL-4 induced cellular senescence as demonstrated by enlarged and flattened morphology, increased granularity, and senescence-associated-β-galactosidase (SA-β-gal) staining. Signal tranducer and activator of transcription 6 (STAT6) and p38 MAPK were found to mediate IL-4-induced growth inhibition and cellular senescence. Both of these molecules were activated by 10 min after IL-4 treatment, and inhibition of their activity or expression prevented growth suppression and cellular senescence induced by IL-4. Inhibiting or silencing either STAT6 or p38 MAPK alone partially reduced the effect of IL-4, whereas inhibiting or silencing both molecules exerted an additive effect and almost completely abrogated the effect of IL-4. Thus STAT6 and p38 MAPK appeared to independently mediate IL-4-induced growth inhibition and cellular senescence. The p21WAF1/CIP1 up-regulation that accompanied growth inhibition and cellular senescence by IL-4 was also attenuated additively when p38 MAPK and STAT6 were silenced. Taken together, these results show that IL-4 induces cellular senescence through independent signaling pathways involving STAT6 and p38 MAPK in some human RCC cell lines. IL-4 can directly inhibit growth of several tumor cell types, but the molecular mechanism is not known. Results: IL-4 induces senescence by increasing p21WAF1/CIP1 expression through STAT6 and p38 MAPK. Conclusion: STAT6 and p38 MAPK play important roles in senescence induction by IL-4. Significance: This is the first report of cellular senescence induction by IL-4 and the responsible mechanism. Interleukin (IL)-4, originally identified as a lymphocyte growth factor, can directly inhibit growth of certain tumor cell types. We reported previously that IL-4 induced cell cycle arrest in G1 phase through an increase in p21WAF1/CIP1 expression in human renal cell carcinoma (RCC) cell lines. In the present study, we investigated the underlying mechanism of IL-4-induced growth inhibition. In four of six human RCC cell lines, including Caki-1, A498, SNU482, and SNU228, IL-4 induced cellular senescence as demonstrated by enlarged and flattened morphology, increased granularity, and senescence-associated-β-galactosidase (SA-β-gal) staining. Signal tranducer and activator of transcription 6 (STAT6) and p38 MAPK were found to mediate IL-4-induced growth inhibition and cellular senescence. Both of these molecules were activated by 10 min after IL-4 treatment, and inhibition of their activity or expression prevented growth suppression and cellular senescence induced by IL-4. Inhibiting or silencing either STAT6 or p38 MAPK alone partially reduced the effect of IL-4, whereas inhibiting or silencing both molecules exerted an additive effect and almost completely abrogated the effect of IL-4. Thus STAT6 and p38 MAPK appeared to independently mediate IL-4-induced growth inhibition and cellular senescence. The p21WAF1/CIP1 up-regulation that accompanied growth inhibition and cellular senescence by IL-4 was also attenuated additively when p38 MAPK and STAT6 were silenced. Taken together, these results show that IL-4 induces cellular senescence through independent signaling pathways involving STAT6 and p38 MAPK in some human RCC cell lines." @default.
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- W2078398006 date "2013-10-01" @default.
- W2078398006 modified "2023-10-17" @default.
- W2078398006 title "Interleukin-4 Induces Senescence in Human Renal Carcinoma Cell Lines through STAT6 and p38 MAPK" @default.
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- W2078398006 doi "https://doi.org/10.1074/jbc.m113.499053" @default.
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