Molecular regulation of IL-6 by asbestos.
Simeonova-P; Flood-L; Luster-M
J Leukoc Biol 1997 Jan; 62(Suppl):14
Pro-inflammatory cytokines and growth factors are involved in the pathophysiological responses of asbestos-related lung diseases. Although interleukin-6 (IL-6) has been characterized as a pleiotropic cytokine with multiple biological activities, its induction and role in asbestos diseases have not been studied. Asbestos fibers were found to stimulate IL-6 secretion and mRNA transcripts in pulmonary type II-like epithelial A549 cells. IL-6 induction was dependent on the intracellular redox-oxidative state since asbestos, as well as H2O2-induced IL-6 secretion was abrogated by intracellular-acting hydroxyl scavengers and N-acetylcysteine. IL-6 induction paralleled increased DNA binding activity to the NF-kB and NF-IL-6 recognized sites in the IL-6 promoter. The NF-kB and NF-IL-6 DNA binding proteins were immunochemically characterized as a heterodimer p65/p50 and a homodimer C/EBP beta, respectively. Asbestos and H2O2-induced DNA binding activity to the NF-kB and NF-IL-6 binding sites of the IL-6 promoter were inhibited by antioxidants. The role of local IL-6 production in the pathophysiological processes of fiber-induced lung disorders was examined. Although less active than fibroblast growth factor IL-6 stimulated in vitro lung fibroblasts growth. 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-induced oxidative stress is involved in the activation of NF-kB and NF-IL-6 transscription factors recognizing IL-6 promoter. The resulting increase in IL-6 expression may be involved in both inflammatory and fibrotic processes in the lung.
Genotoxic-effects; Genes; Asbestos-fibers; Fibrous-dusts; Dust-particles; Particulate-dust
Journal of Leukocyte Biology