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Double-Stranded RNA Induces the Synthesis of Specific Chemokines by Bronchial Epithelial Cells

Departments of Pediatrics and Medicine, University of Wisconsin-Madison Medical School, Madison, Wisconsin

Address correspondence to: James E. Gern, M.D., K4/918 CSC, 600 Highland Avenue, Madison, WI 53792-9988. E-mail: gern{at}medicine.wisc.edu

Virus-induced secretion of proinflammatory chemokines (e.g., regulated on activation, normal T cells expressed and secreted [RANTES], interleukin [IL]-8) by airway epithelial cells helps to initiate antiviral responses and airway inflammation by enhancing inflammatory cell recruitment. To define mechanisms for virus-induced chemokine secretion, monolayers of nontransformed bronchial epithelial cells were transfected or incubated with polydeoxyinosinic-deoxycytidylic acid (synthetic double-stranded [ds] RNA), rhinovirus dsRNA, or single-stranded RNA (ssRNA), and the secretion of selected chemokines was determined. Transfection or incubation with dsRNA, but not ssRNA, significantly enhanced secretion of RANTES and IL-8, but not eotaxin or macrophage inflammatory protein-1. Mechanistically, dsRNA induced and activated dsRNA-dependent protein kinase (PKR), and activated nuclear factor-B and p38 mitogen-activated protein kinase. Furthermore, the PKR inhibitor 2-aminopurine significantly blocked dsRNA-induced RANTES and IL-8 secretion, whereas the p38 mitogen-activated protein kinase inhibitor SB203580 suppressed dsRNA-induced IL-8, but not RANTES. These findings indicate that dsRNA selectively induce the secretion of chemokines such as IL-8 and RANTES, and implicate dsRNA-sensitive signaling proteins in this process. Moreover, these data suggest that this may be an important mechanism for the selective secretion of chemokines by viruses (e.g., rhinovirus, respiratory syncytial virus, influenza) that synthesize dsRNA during replication.

Abbreviations: activator protein-1, AP-1 • bronchial epithelial, BE • double-stranded, ds • enzyme-linked immunosorbent assay, ELISA • interferon, IFN • interleukin, IL • mitogen-activated protein, MAP • macrophage inflammatory protein, MIP • nuclear factor-B, NF-B • polyacrylamide gel electrophoresis, PAGE • phosphate-buffered saline, PBS • dsRNA-dependent protein kinase, PKR • polydeoxyinosinic-deoxycytidylic acid, poly IC • regulated on activation, normal T cells expressed and secreted, RANTES • rhinovirus, RV • sodium dodecyl sulfate, SDS • single-stranded, ss • tumor necrosis factor-, TNF-

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