Interference with intraepithelial TNF-α signaling inhibits CD8 + T-cell-mediated lung injury in influenza infection

Anon Srikiatkhachorn, Jyothi Chintapalli, Jun Liu, Mohammad Jamaluddin, Kevin S. Harrod, Jeffrey A. Whitsett, Richard I. Enelow, Chilakamarti V. Ramana

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)639-645
Number of pages7
JournalViral Immunology
Volume23
Issue number6
DOIs
StatePublished - Dec 1 2010

    Fingerprint

ASJC Scopus subject areas

  • Immunology
  • Molecular Medicine
  • Virology

Cite this

Srikiatkhachorn, A., Chintapalli, J., Liu, J., Jamaluddin, M., Harrod, K. S., Whitsett, J. A., Enelow, R. I., & Ramana, C. V. (2010). Interference with intraepithelial TNF-α signaling inhibits CD8 + T-cell-mediated lung injury in influenza infection. Viral Immunology, 23(6), 639-645. https://doi.org/10.1089/vim.2010.0076