MOLECULAR REGULATION OF IL-6 ACTIVATION BY ASBESTOS IN LUNG EPITHELIAL-CELLS - ROLE OF REACTIVE OXYGEN SPECIES

IL-6 has been characterized as a pleiotropic cytokine with multiple bi ologic activities, but its induction and role in asbestos diseases hav e not been studied, Asbestos fibers were found to stimulate IL-6 expre ssion and secretion in pulmonary type Ii-like epithelial A549 cells as well as in normal human bronchial epithelial cells, IL-6 induction wa s dependent on the intracellular redox-oxidative state, since intracel lular hydroxyl scavengers and N-acetylcysteine, a precursor of glutath ione, abrogated IL-6 secretion by asbestos or H2O2. IL-6 induction par alleled increased DNA binding activity to the nuclear factor-kappa B ( NF-kappa B)- and NF-IL-6-recognized sites in the IL-6 promoter, The NF -kappa B and NF-IL-6 DNA binding proteins were immunochemically charac terized as a heterodimer p65/p50 and a homodimer C/EBP beta, respectiv ely, Stimulation of DNA binding activity to the NF-kappa B and NF-IL-6 binding sites of the IL-6 promoter by asbestos or H2O2 were inhibited by tetramethylthiourea, a hydroxyl radical scavenger, The role of loc al IL-6 production in the pathophysiologic processes of fiber-induced lung disorders was examined, Although less active than fibroblast grow th factor, human rIL-6 also stimulated lung fibroblast growth, as evid enced by increased [H-3]thymidine incorporation. Furthermore, elevated IL-6 levels were found in bronchoalveolar lavage fluids from patients diagnosed with lung fibrosis and work-related histories of long term asbestos exposure, Taken together, the results suggest that asbestos-i nduced oxidative stress is involved in the activation of NF-kappa B an d NF-IL-6 transcription factors, which recognize the IL-6 promoter, Th e resulting increase in IL-6 expression may be involved in both inflam matory and fibrotic processes in the lung.