Double-stranded RNA induces the synthesis of specific chemokines by bronchial epithelial cells.
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-1alpha. Mechanistically, dsRNA induced and activated dsRNA-dependent protein kinase (PKR), and activated nuclear factor-kappaB 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.
Gern
James E
JE
Department of Pediatrics, University of Wisconsin-Madison Medical School, Madison, Wisconsin, USA. gern@medicine.wisc.edu
French
Delores A
DA
Grindle
Kristine A
KA
Brockman-Schneider
Rebecca A
RA
Konno
Shin-Ichi
S
Busse
William W
WW
D001980:Bronchi / Q000166:cytology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis*; D019742:Chemokines, CC / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011119:Polynucleotides / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000138:chemical synthesis / Q000494:pharmacology*; D012367:RNA, Viral / Q000494:pharmacology; D012229:Rhinovirus / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016209:Interleukin-8; D016328:NF-kappa B; D011119:Polynucleotides; D011725:Pyridines; D012330:RNA, Double-Stranded; D012367:RNA, Viral; C052191:poly(dG).poly(rC); D019892:eIF-2 Kinase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580