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J. Biol. Chem., Vol. 280, Issue 25, 24127-24134, June 24, 2005

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The IB Kinase Is a Key Factor in Triggering Influenza A Virus-induced Inflammatory Cytokine Production in Airway Epithelial Cells^*

Daniela Bernasconi, Carla Amici, Simone La Frazia, Angela Ianaro, and M. Gabriella Santoro¶

From the Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome 00133, Italy and Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano, Naples 49-80131, Italy

Influenza A viruses continue to represent a severe threat worldwide, causing large epidemics and pandemics responsible for thousands of deaths every year. Excessive inflammation due to overabundant production of proinflammatory cytokines by airway epithelial cells is considered an important factor in disease pathogenesis. Here we report that influenza A virus induced IB kinase (IKK) activity in human airway epithelial A549 cells, resulting in persistent activation of nuclear factor-B (NF-B), a critical regulator of the inflammatory response. Although lung epithelial cells are highly sensitive to stimulation of the IKK/NF-B pathway by influenza virus infection, NF-B was not activated in several non-pulmonary cells permissive to the virus, indicating a cell-specific response. Moreover, NF-B was not essential for virus replication but triggered the expression of proinflammatory cytokines in infected lung cells and was directly responsible for production of high levels of interleukin-8, a chemokine associated with influenza-induced inflammation and airway pathology. We also report that 9-deoxy-⁹,¹²-13,14-dihydro-prostaglandin D₂, a cyclopentenone prostanoid with therapeutic efficacy against influenza in preclinical studies, was a powerful inhibitor of influenza virus-induced IKK activity and interleukin-8 production by human pulmonary cells. The results identify IKK as an important factor in triggering influenza virus-induced inflammatory reactions in pulmonary epithelium, suggesting novel therapeutic approaches in the treatment of influenza.

Received for publication, December 6, 2004 , and in revised form, April 1, 2005.

^* This work was supported by the Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) (Fondo per gli Investimenti della Ricerca di Base (FIRB) projects) and the Italian Ministry of Public Health (Istituto Superiore di Sanità (ISS) projects). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 39-06-7259-4822; Fax: 39-06-7259-4821; E-mail: santoro{at}bio.uniroma2.it.

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