Differential Expression of Nuclear Factor-κB Mediates Increased Pulmonary Expression of Tumor Necrosis Factor-α and Virus-Induced Asthma

Abstract

Infections with respiratory pathogens such as respiratory syncytial virus and rhinovirus have been associated with the development of long-term chronic airway disease. To better understand the events responsible for this clinical outcome, a rodent model of virus-induced chronic airway disease has been characterized. Upon infection with Sendai virus (parainfluenza virus type-1), Brown Norway (BN) rats develop an asthma-like clinical syndrome, while Fischer 344 (F344) rats fully recover. Our previous studies demonstrated that after infection, tumor necrosis factor-alpha (TNF-alpha) expression is substantially higher in BN rats compared to F344 rats, and this may at least partially mediate the virus-induced airway abnormalities. To investigate the underlying mechanism(s) for the increased TNF-alpha expression, the role of nuclear factor-kappaB (NF-kappaB), an important regulator of TNF-alpha gene transcription, was examined. Supershift electrophoretic mobility shift assays (EMSAs) indicate that normal F344 rats predominantly express the p65 subunit of NF-kappaB in the lungs, and virus infection temporarily increases expression of the p50 subunit. In contrast, normal BN rats have higher expression of the p50 subunit in the pulmonary tract. Upon infection, p50-subunit expression in BN rats increases to levels higher than those observed in virus-infected F344 rats. Interestingly, treatment of infected BN rats with dexamethasone at doses known to prevent virus-induced airway abnormalities increases pulmonary expression of the p65 subunit, and decreases TNF-alpha mRNA levels in the lungs. Furthermore, direct inhibition of TNF-alpha also increases pulmonary expression of p65 in virus-infected BN, but not F344, rats. Taken together, these results suggest that differential expression of NF-kappaB subunits may play an important role in the development of post-viral chronic airway abnormalities.

Local cytokine response upon respiratory syncytial virus infection

“…Accordingly, down-regulation of NF-B activity has been shown to decrease lung inflammation upon infection [78]. This notion is supported by a recent study suggesting that the susceptibility to display an asthma-like syndrome after RSV infection could be due to differential expression of NF-B subunits in the lungs [79].…”

“…For instance, expression of the NF-B p50-subunit was increased in the lungs before and after RSV-infection in susceptible mice [79]. In contrast, animals that fully recovered displayed predominant expression of the NF-B p65-subunit prior to infection, which shifted only moderately to the usage of the p50-subunit after infection (Fig.…”

“…In contrast, animals that fully recovered displayed predominant expression of the NF-B p65-subunit prior to infection, which shifted only moderately to the usage of the p50-subunit after infection (Fig. 2) [79]. Along these lines, rat strains susceptible to long-term chronic airway disease expressed higher levels of the NF-B p50-subunit in the lungs upon viral challenge as compared to strains that fully recover from infection [79].…”

“…2) [79]. Along these lines, rat strains susceptible to long-term chronic airway disease expressed higher levels of the NF-B p50-subunit in the lungs upon viral challenge as compared to strains that fully recover from infection [79]. On the other hand, animals suffering less severe disease were shown to predominantly express the NF-B p65 subunit in the airways, which temporarily shifted to the p50 subunit upon virus infection [78].…”

“…p50 vs. p65), suggesting an important role for the regulation of these transcription factors at shaping inflammation in the lungs [79]. TNF-␣ is a major pro-inflammatory cytokine that can cause chronic inflammatory disease when secreted in large quantities [80] and has been linked to eosinophilia upon RSV-infection [67].…”