Interleukin 4 regulates G1 cell cycle progression in gastric carcinoma cells.

We have previously reported that interleukin 4 (IL-4) inhibits the growth of human gastric carcinoma cells. To investigate the mechanism for this inhibition we analyzed the effect of IL-4 on cell cycle progression of the IL-4-sensitive gastric carcinoma cell line, HTB-135. IL-4 significantly inhibited cell cycle G1-S-phase progression. To assess the postreceptor molecular events that transduced the negative-growth signals by IL-4, we analyzed the expression of cell cycle nuclear-regulating factors such as retinoblastoma gene product (Rbp), c-myc, c-myc protein (c-mycp), and cyclin D1 expression which are known to be regulators of G1-S-phase transition. IL-4 was found to induce an unphosphorylated form of Rbp within 24 h and significantly reduce the phosphorylated form at 48 h. The transition of Rbp to a hypophosphorylated form concurs with the decrease in c-myc gene expression and c-mycp. In addition, we demonstrated that IL-4 down-regulated p34cdc2, a kinase associated with Rbp phosphorylation and cyclin D1. Cyclin D1, considered as a critical nuclear regulatory factor of G0-G1 to S-phase transition was down-regulated 24 and 48 h post-IL-4 treatment as well. These studies suggest that IL-4 inhibits gastric cell proliferation by blocking cell cycle progression by down-regulating several key G0-G1 cell cycle nuclear-regulating factors.