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Journal of Virology, September 2002, p. 9298-9306, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9298-9306.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Release of Macrophage Migration Inhibitory Factor and CXCL8/Interleukin-8 from Lung Epithelial Cells Rendered Necrotic by Influenza A Virus Infection

Ute Arndt,1 Gunther Wennemuth,2 Peter Barth,3 Marianne Nain,1 Yousef Al-Abed,4 Andreas Meinhardt,2 Diethard Gemsa,1 and Michael Bacher1*

Institute of Immunology,1 Institute of Anatomy and Cell Biology,2 Department of Pathology, Philipps-University, Marburg, Germany,3 Laboratory of Medical Chemistry, North Shore Long Island Jewish Research Institute, Manhasset, New York 110304

Received 14 February 2002/ Accepted 7 June 2002

Bronchiolar epithelial cells are the prime targets for influenza A virus infection. It still remains to be clarified which signals are generated from these cells to initiate an immune response. Among chemokines, viral infection of primary lung epithelial cells triggered exclusively the release of CXCL8/interleukin-8 (IL-8), which contrasts with our previous observation that influenza A virus induced in monocytes the expression of mononuclear-leukocyte-attracting chemokines and even suppressed the production of neutrophil-attracting chemokines. Therefore, we speculated that it may be advantageous for respiratory epithelial cells to release primarily neutrophil-attracting CXCL8/IL-8 since neutrophils rapidly remove necrotic debris and are the first line of defense against bacterial superinfections. This concept has also been supported by our finding that influenza A virus infection led to necrosis of lung epithelial cells. This is in striking contrast to previous studies where influenza A virus infection induced apoptosis in monocytes and epithelial cells from origins other than the lung. Thus, the cell type instead of the virus determines which death pathway will be followed. In addition to the release of CXCL8/IL-8, we obtained a massive release of macrophage migration inhibitory factor (MIF) from virus-infected lung cells. However, whereas the CXCL8/IL-8 secretion was accompanied by induced gene activation, the transcription rate of MIF remained unchanged during the infection course and the virus-induced MIF release was predominantly a discharge from intracellular stores, suggesting that MIF is passively released upon cell death. Despite virus induced necrosis, the passively liberated MIF remained bioactive. Considering the well-established immunostimulatory effects of MIF on different leukocyte subsets, is its very likely that enhanced levels of MIF may contribute to the host immune response during the acute phase of influenza A virus infection in humans.

* Corresponding author. Mailing address: Institute of Immunology, Robert Koch-Str. 17, 35037 Marburg, Germany. Phone: 49-6421-2865314. Fax: 49-6421-2866813. E-mail: bacher{at}mailer.uni-marburg.de.

Journal of Virology, September 2002, p. 9298-9306, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9298-9306.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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