Objective To explore the immunopathologic mechanism underlying the inflammatory response after severe acute respiratory syndrome（SARS） invasion.Methods Pathway focused cDNA microarrays were employed for comparision of the gene expression patterns in 16HBEs treated with interferon-γ(IFN-γ) or the S protein of SARS-CoV.The S proteins were administered to BALB/c mice and the pathological changes of lung and spleen were observed.Results S protein activated JAK/STAT signal pathway in the 16HBEs with inducible protein 10（IP-10） gene expression，and the specific inhibitors of the JAK/STAT signal pathway were able to downregulate the induction of IP-10.The mice instilled intracheally with S proteins revealed obvious acute diffuse damage and increased IP-10 expression and CD68+ macrophages infiltration in both lung and spleen tissues.In contrast，the treatment with JAK3 inhibitors attenuated lung and spleen injury in the mice.Conclusion Our findings support that the activation of JAK/STAT pathway induced by SARS-CoV S protein plays a key role in promotion of an IFN -γ inducible chemokine cascade，which can help in the development of novel drug and therapeutics for prevention and treatment of SARS.