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Viral regulation of inflammatory cytokines in epithelial cells: an alternative signalling pathway
  1. I S Patel
  1. Specialist Registrar, London

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Respiratory viruses primarily target the bronchial epithelium and induce the expression of several inflammatory cytokines and chemokines. These include tumour necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) which are key regulatory factors in the early induction of inflammation and Th1/Th2 immune responses. A number of cellular signalling pathways are thought to play a role in this context including nuclear factor-κB (NF-κB), a ubiquitous transcription factor which has been shown to be important in inflammatory cytokine expression. However, the molecular mechanisms governing virus induced epithelial inflammatory responses are largely unknown.

In this study both primary human bronchial epithelial cells and cell lines were cultured and infected with either wild-type reovirus or respiratory syncytial virus (RSV). Cells were also treated with double stranded RNA (dsRNA), used as a viral mimetic. Total cellular RNA was then extracted and subjected to RT-PCR using specific primers to quantify the levels of the cytokines TNF-α and IL-1β produced. Western blot analysis was performed to detect activation of different signalling molecules.

Infection of epithelial cells with either virus induced inflammatory cytokines in a time-dependent manner. dsRNA treatment stimulated cytokine production similarly. Interestingly, inhibition of NF-κB did not significantly reduce viral or dsRNA induction of either cytokine. However, viral infection and dsRNA treatment were shown to activate the p38 mitogen-activated protein K (p38 MAPK) signalling pathway in epithelial cells. This kinase is important in the induction of innate immune responses and the activation of adaptive immune lymphocytes. Inhibition of p38 MAPK by two different pharmacological inhibitors showed that expression of dsRNA induced TNF-α and IL-1β required activation of this signalling protein.

This study has shown that signalling pathways distinct from NF-κB may be important in early cytokine responses to viral infection, and NF-κB activation may be less pivotal than previously thought. This is supported by similar findings from a recent study of cytokine induction by human rhinovirus infection of bronchial epithelial cells (

). Studies examining other possible signalling pathways are now needed to further our understanding of the cellular mechanisms of virus induced airway inflammation.

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