Asthma is an economically important disease, with exacerbations causing significant
morbidity and morality. Viral infections cause ~80% of asthma exacerbations; the
majority of which are attributed to rhinovirus infection. How rhinovirus infection leads to
an acute asthma exacerbation is incompletely understood. The up-regulation of proinflammatory
cytokines/chemokines from rhinovirus infected bronchial epithelial cells
and an impaired ability of rhinovirus infected asthmatic bronchial epithelial cells to
produce type I interferon-β and type III interferon-λs, are believed to contribute. This
study aimed to investigate differences in the signalling requirements of rhinovirusinduced
pro-inflammatory cytokines/chemokines from those of IFN-β/IFN-λ. The viral
pattern recognition receptors, signalling intermediates and transcription factors required
by rhinovirus to induce pro-inflammatory cytokine/chemokine and IFN-β/IFN-λ
expression were explored using short interfering RNA, constitutive activation/overexpression
of signalling molecules and IFN-β promoter reporter mapping experiments.
The viral pattern recognition receptors RIG-I, MDA5 and TLR3 were required for
rhinovirus-induced pro-inflammatory cytokines IL-8/CXCL8, ENA-78/CXCL5, IL-6
RANTES/CCL5, IP-10/CXCL10 and IFN-β expression. Only MDA5 and TLR3 are
required for rhinovirus-induced IFN-λ expression. Whilst having common signalling
intermediates, the adaptor protein TRAF6, the kinases JNK2 and PI3Kα and the
transcription factor NF-kB p65 were not required for rhinovirus-induced IFN-β/λ
expression, but were required for rhinovirus induction of some/all of the proinflammatory
cytokines measured. IRF3 was the only transcription factor identified to be
commonly required for rhinovirus-induced expression of IFN-β and IFNλ-s. These
findings support the hypothesis that the induction of IFN-β/λ and pro-inflammatory
cytokines/chemokines, by rhinovirus, requires one or more distinct signalling molecules,
and/or transcription factors. TRAF6, JNK2, PI3Kα and NF-kB p65 are potential novel
therapeutic targets for rhinovirus-induced asthma exacerbations, the inhibition of which
may suppress the detrimental actions of pro-inflammatory cytokines/chemokines without
inhibiting IFN-β/λ production in asthmatic bronchial epithelial cells.