Autocrine interleukin-1 beta production in leukemia: Evidence for the involvement of mutated RAS

Interleukin (IL)-1 beta is constitutively expressed in many leukemias and o perates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic l eukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-IP and have mutations in the K-RAS and N-RAS genes, respectiv ely. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1 beta promoter elements [nuclear factor (NF)-IL6/CREB, NFB 1, NF kappa B, and NF-IL6], consistent with the activation of an upstream s ignaling pathway. To determine whether activated Ras was involved, two stru cturally distinct classes of farnesyltransferase (FTase) inhibitors (the mo noterpenes and a peptidomimetic) and an adenoviral vector expressing antise nse targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a conce ntration-dependent decrease in both NF-IL6/CREB binding to the IL-1 beta pr omoter and IL-1 beta protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21(Ras) and IL-1 beta protein levels. Growth suppression was observed after FTase i nhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1 beta to the cultures, Our observations sug gest that mutated RAS genes may mediate autocrine IL-1 beta production in s ome leukemias by stimulating signal transduction pathways that activate the IL-1 beta promoter.