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Tuesday, November 5, 2013

Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor кB and c-Jun N-terminal kinase activation

Inhaled glucocorticoids are often highly effective in treating symptoms of asthma exacerbations, however they are ineffective at treating and preventing exacerbations brought on by rhinovirus infection, especially in children.  Glucocorticoids act by binding to glucocorticoid receptors (GR) α which become activated and translocate to the nucleus, leading to the activation of down-stream anti-inflammatory pathways.  Papi et al sought to determine the mechanistic actions of glucocorticoids during rhinovirus infection by studying factors in these anti-inflammatory pathways (J Allergy Clin Immunol 2013; 132(5): 1075-1085).

Using a variety of assays and human bronchial epithelial cells, the authors determined that the rhinovirus RV-16 reduces the ability of dexamethasone to inhibit the pro-inflammatory cytokine IL-1β induction of the chemokine CXCL8.  They went on to show that there is an RV-16 dependent impairment of dexamethasone-induced GRα nuclear translocation that is mediated by the transcription factor NFкB p65 as well as the c-JUN N-terminal Kinase, JNK-1, both pro-inflammatory pathways.  To solidify this finding, Papi attempted to reverse the RV-16 induced attenuation of GR nuclear translocation by dexamethasone with inhibitors of NFкB and JNK. Their results indicate that independently, both inhibitors partially rescued the impairment and the combination of both inhibitors totally restored dexamethasone sensitivity. The authors show that rhinovirus infection inhibits glucocorticoid mechanisms of action and impair both the transactivation and transrepression activities of dexamethasone, implying that rhinovirus infection targets an upstream aspect of GR activation. 

These finding suggest a novel molecular mechanism for rhinoviruses, the biggest trigger of asthma exacerbations, to impair the ability of glucocorticoids to control airway inflammation.  These data indicate a strategy through which rhinovirus infection can overcome the anti-inflammatory defense but also indicate approaches that might reverse this process.  The discovery of completely inhibiting both NFкB and JNK pathways reverses glucocorticoid resistance identifies new therapeutic approaches for asthma and rhinoviruses in general for which there is no effective treatment available.

Questions for the authors:
Are there other markers or pathways that are involved that could be considered therapeutic approaches for treatment?
Yes, it is possible that the mechanisms by which rhinovirus inhibit corticosteroid activity involves the activation of other pro-inflammatory pathways, as 1) rhinovirus induces the production of multiple inflammatory mediators; 2) rhinovirus inhibits an upstream step of the mechanism of action of corticosteroids. We analyzed the keys/main mediators, but many other could be affected.

Could there be other pro-inflammatory cytokines that are up-regulated that amplify the effect of rhinoviruses?
Several pro-inflammatory mediators are induced by rhinovirus infection (Hansell TT. Lancet. 2013). They are likely affected by the mechanisms we described in the study as they are upstream steps of the mechanism of action of corticosteroids.

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