IL-6 up-regulates Mcl-1 in human myeloma cells through JAK/STAT rather than Ras/MAP kinase pathway

Mcl-1 is an anti-apoptotic member of the Bcl-2 family which is tightly regu lated during myeloid and B cell differentiation. We have recently reported that Mcl-1 is expressed in human myeloma cells and that Mcl-1 and Bcl-x(L) expression are correlated. In the current study, we demonstrate that IL-6, a survival factor for the human myeloma cell line MDN, rapidly upregulates Mcl-1 whereas it has no effect on Bcl-2 protein level. In MDN cells, IL-6 i nduces both extracellular signal-regulated protein kinase (ERK)1,2 and STAT 3 activation whereas STAT1 and STAT5 activation remains undetectable. Furth ermore, while investigating the IL-6 signaling pathway leading to Mcl-1 up- regulation, we show that a janus kinase (JAK)-2 inhibitor is able to inhibi t both STAT3 activation and Mcl-1 up-regulation whereas an MAP/ERK kinase ( MEK) inhibitor has no effect. In conclusion, our data suggest the involveme nt of the JAK/STAT pathway but not of the Ras/mitogen-activated protein (MA P) kinase pathway in IL-6-induced Mcl-1 up-regulation.