Autocrine regulation of interleukin-8 by interleukin-1 alpha in respiratory syncytial virus-infected pulmonary epithelial cells in vitro

Respiratory epithelial cells infected with respiratory syncytial virus (RSV ) produce interleukin-8 (IL-8); however, the mechanisms of RSV-induced regu lation 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 cell s (cRSV) induced IL-8 production in fresh A549 cultures within 4 hr of infe ction. Furthermore, cRSV that had been rendered non-infectious by ultraviol et-irradiation (UV-cRSV) or ribavirin treatment also induced an increased p roduction of IL-8 in fresh A549 cells, suggesting that RSV induced the synt hesis 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-1 alpha, IL-1-beta and tumour necrosis factor-alpha (TNF-alpha), which by themselve s are known to induce the synthesis of IL-8. Preincubation of UV-cRSV or si multaneous incubation of pRSV with recombinant IL-I receptor antagonist alm ost completely blocked (95-98%) the production of IL-8 by A549 cells. Furth ermore, incubation with neutralizing antibodies against IL-1 alpha, IL-1 be ta and TNF-alpha showed that IL-1 alpha was the predominant soluble mediato r that enhanced the mRNA expression and synthesis of IL-8. IL-1 beta and TN F-alpha 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 epit helial cells that is primarily mediated by IL-1 alpha. In clinical settings , inhibitors of IL-1 alpha may be useful in suppressing inflammation due to IL-1 alpha as well as IL-8.