INTERLEUKIN-4 REGULATES G(1) CELL-CYCLE PROGRESSION IN GASTRIC-CARCINOMA CELL

We have previously reported that interleukin 4 (IL-4) inhibits the gro wth of human gastric carcinoma cells. To investigate the mechanism for this inhibition we analyzed the effect of IL-4 on cell cycle progress ion of the IL-4-sensitive gastric carcinoma cell line, HTB-135. IL-4 s ignificantly inhibited cell cycle G(1)-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-regu lating factors such as retinoblastoma gene product (Rbp), c-myc, c-myc protein (c-mycp), and cyclin D1 expression which are known to be regu lators of G(1)-S-phase transition. IL-4 was found to induce an unphosp horylated form of Rbp within 24 h and significantly reduce the phospho rylated form at 48 h. The transition of Rbp to a hypophosphorylated fo rm concurs with the decrease in c-myc gene expression and c-mycp. In a ddition, we demonstrated that IL-4 down-regulated p34(cdc2), a kinase associated with Rbp phosphorylation and cyclin D1. Cyclin D1, consider ed as a critical nuclear regulatory factor of G(0)-G(1) to S-phase tra nsition was down-regulated 24 and 48 h post-IL-4 treatment as well. Th ese studies suggest that IL-4 inhibits gastric cell proliferation by b locking cell cycle progression by down-regulating several key G(0)-G(1 ) cell cycle nuclear-regulating factors.