Respiratory epithelial cells infected with respiratory syncytial virus (RSV) produce interleukin-8 (IL-8); however, the mechanisms of RSV-induced regulation of IL-8 are poorly understood. In the present study, the regulation of IL-8 by RSV was evaluated using pulmonary type II-like epithelials (A549). Live purified RSV (pRSV) induced a significant increase in IL-8 after 8 hr of exposure, while conditioned supernatants from pRSV- infected A549 cells (cRSV) induced IL-8 production in fresh A549 cultures within 4 hr of infection. Furthermore, cRSV that had been rendered non- infectious by ultraviolet-irradiation (UV-cRSV) or ribavirin treatment also induced an increased production of IL-8 in fresh A549 cells, suggesting that RSV induced the synthesis of a soluble mediator(s) which in turn enhanced the synthesis of IL-8. We have previously shown that RSV-infected A549 cells produce IL-1α, IL-1β and tumour necrosis factor-α (TNF-α), which by themselves are known to induce the synthesis of IL-8. Preincubation of UV- cRSV or simultaneous incubation of pRSV with recombinant IL-1 receptor antagonist almost completely blocked (95-98%) the production of IL-8 by A549 cells. Furthermore, incubation with neutralizing antibodies against IL-1α, IL-1β and TNF-α showed that IL-1α was the predominant soluble mediator that enhanced the mRNA expression and synthesis of IL-8. IL-1β and TNF-α induced the synthesis of IL-8 at 24 hr, but partially inhibited the synthesis at 48 hr. In summary, these experiments provide direct evidence for an autocrine mechanism of enhanced IL-8 production in RSV-infected epithelial cells that is primarily mediated by IL-1α. In clinical settings, inhibitors of IL-1α may be useful in suppressing inflammation due to IL-1α as well as IL-8.
ASJC Scopus subject areas
- Immunology and Allergy