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

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

doi:10.1074/jbc.m413726200

Simone La Frazia, Carla Amici + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m413726200

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Abstract

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 IkappaB kinase (IKK) activity in human airway epithelial A549 cells, resulting in persistent activation of nuclear factor-kappaB (NF-kappaB), a critical regulator of the inflammatory response. Although lung epithelial cells are highly sensitive to stimulation of the IKK/NF-kappaB pathway by influenza virus infection, NF-kappaB was not activated in several non-pulmonary cells permissive to the virus, indicating a cell-specific response. Moreover, NF-kappaB 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-delta9,delta12-13,14-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.

Highlights

Influenza, a highly contagious acute respiratory illness that affects all age groups, is responsible for an average of 36,000 deaths and 114,000 hospitalizations per year in the United States alone [1]
The mechanisms underlying the expression of symptoms and the development of secondary complications that may result in respiratory failure are still not well understood, excessive inflammation due to overabundant production of proinflammatory cytokines and lung inflammatory infiltrates is considered an important factor in disease pathogenesis [2,3,4]
Influenza A Virus Infection Induces nuclear factor-␬B (NF-␬B) Activity in Human Airway Epithelial Cells via Stimulation of the I␬B Kinase—As reported for several human viral pathogens, orthomyxoviruses are able to activate NF-␬B in infected cells (7, 18 –19); the molecular mechanisms involved in NF-␬B activation by influenza virus have not yet been elucidated

Summary

Introduction

A highly contagious acute respiratory illness that affects all age groups, is responsible for an average of 36,000 deaths and 114,000 hospitalizations per year in the United States alone [1]. We report that influenza A virus induced I␬B 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.

Results

Conclusion