title: Interference with intraepithelial TNF-α signaling inhibits CD8(+) T-cell-mediated lung injury in influenza infection.
abstract: CD8(+) T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-α expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8(+) T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-α signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8(+) T-cell recognition, or to TNF-α. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-κB activity, which was independent of Iκ-Bα degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3β, and the p65 subunit of NF-κB, as well as recruitment of NF-κB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-κB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection.
authors.affiliation: Center for Infectious Disease and Vaccine Research, University of Massachusetts, Worcester, Massachusetts, USA.
authors.forename: Anon
authors.initials: A
authors.lastname: Srikiatkhachorn
authors.forename: Jyothi
authors.initials: J
authors.lastname: Chintapalli
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jamaluddin
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Richard I
authors.initials: RI
authors.lastname: Enelow
authors.forename: Chilakamarti V
authors.initials: CV
authors.lastname: Ramana
mesh_terms: D017503:Adenovirus E3 Proteins / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018932:Chemokine CCL2 / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology; D055370:Lung Injury / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D017503:Adenovirus E3 Proteins; D018932:Chemokine CCL2; D018925:Chemokines; C509184:E3 14.7K protein, Adenovirus; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha