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Journal of Virology, September 2000, p. 8425-8433, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Synergistic Upregulation of Interleukin-8 Secretion from Pulmonary Epithelial Cells by Direct and Monocyte-Dependent Effects of Respiratory Syncytial Virus Infection

Lynette H. Thomas,1 Melissa I. Y. Wickremasinghe,1 Mike Sharland,2 and Jon S. Friedland1,*

Department of Infectious Diseases, Imperial College of Science, Technology and Medicine, Hammersmith Campus, London W12 0NN,1 and Pediatric Infectious Diseases Unit, St. George's Hospital Medical School, London SW17 0RE,2 United Kingdom

Received 20 January 2000/Accepted 5 June 2000

Respiratory syncytial virus (RSV) infection is the major cause of severe bronchiolitis in infants. Pathology of this infection is partly due to excessive proinflammatory leukocyte influx mediated by chemokines. Although direct infection of the respiratory epithelium by RSV may induce chemokine secretion, little is known about the role of cytokine networks. We investigated the effects of conditioned medium (CM) from RSV-infected monocytes (RSV-CM) on respiratory epithelial (A549) cell chemokine release. RSV-CM, but not control CM (both at a 1:5 dilution), stimulated interleukin-8 (IL-8) secretion from A549 cells within 2 h, and secretion increased over 72 h to 11,360 ± 1,090 pg/ml without affecting cell viability. In contrast, RSV-CM had only a small effect on RANTES secretion. RSV-CM interacted with direct RSV infection to synergistically amplify IL-8 secretion from respiratory epithelial cells (levels of secretion at 48 h were as follows: RSV-CM alone, 8,140 ± 2,160 pg/ml; RSV alone, 12,170 ± 300 pg/ml; RSV-CM plus RSV, 27,040 ± 5,260 pg/ml; P < 0.05). RSV-CM induced degradation of Ikappa Balpha within 5 min but did not affect Ikappa Bbeta . RSV-CM activated transient nuclear binding of NF-kappa B within 1 h, while activation of NF-IL6 was delayed until 8 h and was still detectable at 24 h. Promoter-reporter analysis demonstrated that NF-kappa B binding was essential and that NF-IL6 was important for IL-8 promoter activity in RSV-CM-activated cells. Blocking experiments revealed that the effects of RSV-CM depended on monocyte-derived IL-1 but that tumor necrosis factor alpha was not involved in this network. In summary, RSV infection of monocytes results in and amplifies direct RSV-mediated IL-8 secretion from respiratory epithelial cells by an NF-kappa B-dependent, NF-IL6-requiring mechanism.

* Corresponding author. Mailing address: Department of Infectious Diseases, Imperial College of Science, Technology and Medicine (Hammersmith Campus), London W12 0NN, United Kingdom. Fax: 44 20 8383 3394. E-mail: j.friedland{at}ic.ac.uk.

Journal of Virology, September 2000, p. 8425-8433, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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