IL-5-induced migration via ERK1/2-mediated MMP-9 expression by inducing activation of NF-κB in HT1376 cells.

Interleukin-5 (IL-5) plays an important role in the growth and differentiation of human B cells and eosinophils. However, little is known about the effect of IL-5 on cancer cells. In this study, we investigated the molecular mechanisms involved in the IL-5-induced migration of HT1376 bladder cancer cells. Our results indicated that IL-5 significantly enhanced migration and MMP-9 expression in HT1376 cells. We also found that IL-5 induces transcriptional activation of the binding of NF-κB and AP-1, which are two important nuclear transcription factors that are linked to MMP-9 expression in HT1376 cells. In subsequent experiments, we found activation of ERK1/2 in IL-5-treated HT1376 cells. To examine the involvement of the ERK1/2 signaling pathway on IL-5-induced cell responses, we pretreated HT1376 cells with the ERK1/2 inhibitor U0126 followed by IL-5 treatment. The results showed that U0126 treatment inhibited migration of IL-5-treated HT1376 cells. Moreover, IL-5-stimulated MMP-9 expression was suppressed by the addition of U0126. Inhibition of ERK1/2 function consistently rescued transcriptional activity of NF-κB, without altering AP-1 activation, in IL-5-treated cells. Finally, inhibition of the IL-5-specific receptor IL-5Rα by small interfering RNA (siRNA) suppressed migration, ERK1/2 activation, MMP-9 expression and binding activation of NF-κB in IL-5-treated HT1376 cells. The results of the present study indicate that the IL-28A/IL-28AR1 dyad induces cell migration through ERK1/2-mediated expression of MMP-9 by binding activation of NF-κB in bladder cancer cells. In conclusion, these novel findings indicate that binding of IL-5 to IL-5Rα plays a critical role in MMP-9 expression, which may be involved in the migration of bladder cancer.