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Induction of IL-8 Release in Lung Cells via Activator Protein-1 by Recombinant Baculovirus Displaying Severe Acute Respiratory Syndrome-Coronavirus Spike Proteins: Identification of Two Functional Regions¹

Ya-Jen Chang^2,*, Catherine Y.-Y. Liu^2,, Bor-Luen Chiang, Yu-Chan Chao^2,3, and Ching-Chow Chen^3,*

Departments of ^* Pharmacology and Pediatrics, College of Medicine, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan; and Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan

The inflammatory response and the intracellular signaling pathway induced by severe acute respiratory syndrome (SARS)-coronavirus (CoV) were studied in lung epithelial cells and fibroblasts. SARS-CoV spike (S) protein-encoding plasmid induced activations of IL-8 promoter and AP-1, but not NF-B in these cells. Mutation of the AP-1, not the B site, abolished the SARS-CoV S protein-induced IL-8 promoter activity. IL-8 release was effectively induced by vAtEpGS688, a baculovirus exhibiting the aa 17–688 fragment of S protein, and this induction was attenuated by the angiotensin-converting enzyme 2 Ab. Recombinant baculovirus expressing different deletion and insertion fragments identified the functional region of S protein from aa 324–688 (particularly the N-terminal aa 324–488 and the C-terminal aa 609–688), which is responsible for IL-8 production. Activations of AP-1 DNA-protein binding and MAPKs after vAtEpGS688 transduction were demonstrated, and SARS-CoV S protein-induced IL-8 promoter activity was inhibited by the specific inhibitors of MAPK cascades. These results suggested that the S protein of SARS-CoV could induce release of IL-8 in the lung cells via activations of MAPKs and AP-1. The identification of the functional domain for IL-8 release will provide for the drug design on targeting specific sequence domains of S protein responsible for initiating the inflammatory response.

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