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.
KeywordsAlveolar Macrophage Idiopathic Pulmonary Fibrosis Interstitial Lung Disease Lower Respiratory Tract Leucine Zipper
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