Involvement of NF-κB in silica-induced cyclooxygenase II gene expression in rat alveolar macrophages

The role of nuclear factor (NF)-κB transcription factor in silica- induced cyclooxygenase (COX) II gene expression was examined in the rat alveolar macrophage cell line NR8383. Our results indicate that NF-κB can be activated in this cell line by silica exposure. Suppression of NF-κB activation in these cells leads to an attenuation of COX II mRNA accumulation induced by silica. Using an electrophoretic mobility shift assay and a reporter gene assay, we provide evidence that at least two κB sites in the 5'-flanking region of the rat COX II gene are involved for silica-induced transcriptional control of the COX II gene. The first motif, -404 GGGGATTCCC -395, is absolutely conserved in sequence and is localized in a similar position among the COX II genes found in humans, rats, and mice. The second motif, -91 GGGGAAAGCC -82, was conserved only in the mouse and rat COX II genes in sequence and in location. Aspirin, a COX inhibitor, was shown to suppress silica-induced NF-κB activation. However, prostaglandin E₂, one of the important downstream reaction products catalyzed by the COX enzyme, was also shown to attenuate silica-induced NF-κB activation by retarding the degradation of silica-induced inhibitor NF-κB. These results suggest that an interdependent regulation may exist between NF-κB activation and COX or its products.