Mucin expression in CF via IL-6,
IL-17 signaling pathways
Cystic Fibrosis (CF) is a potentially lethal genetic disease that typically results in
the development of bronchial inflammation, bronchiectasis, the progressive loss of lung
function and ultimately death .
CF was initially called "mucoviscidosis" because of copious amounts of "mucoproteins"
in the respiratory and gastrointestinal tracts of CF patients .
CF is a recessive genetic disease caused by mutations in the
CFTR gene, which encodes the Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR), a chloride channel. Expression
of mutant CFTR in CF respiratory cells results in defective
chloride secretion and elevated sodium absorption, resulting in altered salt
concentrations in airway secretions. Alterations in mucus volume may impact mucus
hydration, and thus the rheology of CF airway mucus to increase susceptibility to
infection in CF airways. Lack of functional CFTR in lung
cells could engender a hyperinflammatory state that alters homeostasis in CF airways.
Inflammatory mediators in the airways of CF can enhance expression of mucin genes,
contributing to recurring cycles of infection followed by increased expression of mucins
that culminates in airway obstruction with mucus .
Pseudomonas aeruginosa is the predominant pathogen of CF
chronic lung infection . Reduced secretion of chloride and fluid
hydration, as well as excessive secretion of mucins, produce a biological matrix that
facilitates growth of P. aeruginosa in biofilm .
Mucus/gel-forming mucins are secreted by airway cells, and these mucins are subject to
regulation by CF inflammatory stimuli. Mucin 5AC and
Mucin 5B have been identified as major gel-forming
In normal human airways, Mucin 5AC is mainly expressed in
surface goblet epithelial cells, whereas Mucin 5B is
predominantly expressed in mucous cells of submucosal glands , , , . However, Mucin 5B
gene products in diseased airways (e.g. in CF or asthma) are also found in
the surface epithelium, rather than just being limited to the submucosal glands , , , . The expression of
Mucin 5B might be a result of goblet cell hyperplasia and
mucus hypersecretion associated with various airway diseases , .
A wide variety of stimuli present in the airways of patients with CF (eg,
Pseudomonas aeruginosa components and proinflammatory
cytokines) are known to cause mucin overproduction.
P. aeruginosa components flagellin
(Flagellin P. aeruginosa) and pilin (PilA P.
aeruginosa) are recognized by the surface receptors: asialo-GM1
ganglioside (asialo-ganglioside GA1) and Toll-like receptors
(TLRs) , , .
Flagellin (P. aeruginosa) is recognized by
TLR5 . Flagellin (P.
and PilA (P. aeruginosa) 
bind bacteria to the host cell glycolipid receptor, asialo-ganglioside
GA1. TLR2 forms a receptor complex with
asialo-ganglioside GA1 and activates
NF-kB signaling , , . P. aeruginosa products have been reported to
upregulate mucin genes expression , .
Epithelial response to CF bacterial ligands is mediated by TLRs and also results
in the expression of
proinflammatory cytokines, including Interleukin 6
IL-6 can induce T-cells to produce Interleukin
IL-17 via Janus Kinase 2
(Jak2)/ Signal Transducer and Activator of Transcription 3
(STAT3)/ Retinoic Acid Receptor-Related Orphan Receptor
Gamma-T (ROR-gamma) pathway , . ROR-gamma is specific transcriptional regulator,
critical for the expression of two members of Interleukin-17 family, IL-17A
(IL-17) and IL-17F , .
IL-17 is a pro-inflammatory cytokine that is secreted
primarily by T cells, while IL-6 is secreted by a wide
variety of cells including inflammatory (e.g. T-cells, macrophages), stromal (e.g.
fibroblast, smooth muscle), and epithelial cells (e.g. airway, renal tubular) , .
In the diseased airway epithelium, both IL-6 and
IL-17 are involved in the expression of mucin genes,
Mucin 5AC and Mucin 5B.
IL-6 is proposed to induce the expression of
Mucin 5B, probably via
Jak2/ STAT3 signaling and
ERK1/2 pathway , .
Little is known about the mechanisms of IL-17 receptor
signaling. IL-17 signals through the Interleukin 17 Receptor
A (IL-17 receptor) that can associate with Interleukin 17
Receptor C (IL-17RC) to form a multimeric receptor complex
. IL-17RC binds both
IL-17F and IL-17 . Upon stimulation with IL-17, TRAF3 Interacting
Protein 2 (CIKS) is supposed to be recruited to
IL-17 receptor, followed by activation of
TRAF6 and Mitogen-Activated Protein Kinase Kinase Kinase 7
(TAK1), which mediate downstream activation of transcription
factor NF-kB , .
Because IL-17 signaling results in the
NF-kB-dependent induction of
IL-6, Mucin 5B expression is at
least partly upregulated by IL-17 through IL-6
by JAK2-dependent autocrine/paracrine loop
Expression of Mucin 5AC and Mucin
5B in response to IL-17 has also been
proposed to depend on JAK2/
STAT3 and ERK1/2 signaling
, , . Several transcription factors,
including NF-kB, c-Jun/c-Fos
and SP1, can be involved
in Mucin 5AC and Mucin 5B
transcription , .
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