Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2

Infection with adenovirus serotype 7 (Ad7) frequently causes lower respirat ory pneumonia and is associated with severe lung inflammation and neutrophi l infiltration. Earlier studies indicated release of proinflammatory cytoki nes, specifically interleukin-8 (IL-8), by pulmonary epithelial cells follo wing infection by Ad7. However, the mechanism of IL-8 induction by Ad7 is u nclear. We have explored the role of the Ras/Raf/MEK/Erk pathway in the Ad7 -associated induction of IL-8 using a model system of A549 epithelial cells . We found that Ad7 infection induced a rapid activation of epithelial cell -derived Erk. The MEK-specific inhibitors PD98059 and U0126 blocked Erk act ivation and release of IL-8 following infection with Ad7. Treatment with PD 98059 is cytostatic and not cytotoxic, as treated cells regain the ability to phosphorylate Erk and secrete IL-8 after removal of the drug. The expres sion of a mutated form of Ras in A549 epithelial cells blocked the inductio n of IL-8 promoter activity, and MEK inhibitor blocked induction of IL-8 mR NA. These results suggest that the Ras/Raf/MEK/Erk pathway is necessary for the Ad7 induction of IL-8 and that induction occurs at the level of transc ription. Further, the kinetics of Erk activation and IL-8 induction suggest that an early viral event, such as receptor binding, may be responsible fo r the observed inflammatory response.