Antiviral immune responses in H5N1-infected human lung tissue and possible mechanisms underlying the hyperproduction of interferon-inducible protein IP-10

► Increased expression of IFN-α, MxA, and IP-10 was detected in H5N1-infected lung. ► Several evidences strongly suggest the role of IP-10 in severity of H5N1 diseases. ► A complex interplay of H5N1 infection, TNF-α and IFN-α enhanced IP-10 response. ► Methylprednisolone inefficiently blocked IP-10 production. ► This data may explain its ineffectiveness in the treatment of H5N1 infection. Information on the immune response against H5N1 within the lung is lacking. Here we describe the sustained antiviral immune responses, as indicated by the expression of MxA protein and IFN-α mRNA, in autopsy lung tissue from an H5N1-infected patient. H5N1 infection of primary bronchial/tracheal epithelial cells and lung microvascular endothelial cells induced IP-10, and also up-regulated the retinoic acid-inducible gene-I (RIG-I). Down-regulation of RIG-I gene expression decreased IP-10 response. Co-culturing of H5N1-infected pulmonary cells with TNF-α led to synergistically enhanced production of IP-10. In the absence of viral infection, TNF-α and IFN-α also synergistically enhanced IP-10 response. Methylprednisolone showed only a partial inhibitory effect on this chemokine response. Our findings strongly suggest that both the H5N1 virus and the locally produced antiviral cytokines; IFN-α and TNF-α may have an important role in inducing IP-10 hyperresponse, leading to inflammatory damage in infected lung.