Transcriptional Regulation of IL-1ß and IL-6 by TNF-α in Asbestosis is Mediated by NF-IL6-like Motifs
Asbestosis is an inflammatory and fibrotic interstitial lung disease characterized by a lower respiratory tract alveolitis and bronchiolitis with increased macrophages, lymphocytes, and neutrophils. The alveolar macrophages have a morphological appearance of activation and spontaneously secrete exaggerated quantities of growth factors, matrix proteins, and cytokines. We performed bronchoalveolar lavage of nine asbestos insulators (category ≥ 1/0 parenchymal opacities) and five normal controls finding increased release into 18 hr supernatants of tumor necrosis factor-α (TNF-α asbestos-exposed 953 ± 192 pg/ml vs normals 290 ± 38 pg/ml, p < 0.005) and interleukin-1ß (IL-1ß asbestosexposed 760 ± 120 pg/ml vs normals 138 ± 24 pg/ml, p < 0.001). Since TNF-α is also a potent mediator of fibrosis in animal models of silicosis, we evaluated its ability to stimulate other cytokines. TNF-α maximally stimulated a -130/+15 IL-1ß genomic fragment and a -158/-49 IL-6 fragment using the CAT assay. We found two NF-IL6 motifs in these fragments that mediated transcription in an independent manner. Interestingly, the IL-6 gene had a NF-κB motif downstream of the NF-IL6 sites that appeared to be even more potent. We also identified NF-IL6 sites near the transcription start site of IL-8 and in the promoter region of TNF-α. The NF-IL6 motifs belong to a family of nuclear binding proteins characterized by a leucine zipper and may play a role in inflammation by stimulating cytokine production contributing to an acute phase response localized to the lower respiratory tract.
KeywordsDust Superoxide Tuberculosis Electrophoresis Leucine
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