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.