Mucin expression in CF via TLRs, EGFR signaling
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 increase 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 .
Secretory mucus/gel-forming mucins (Mucin 2,
Mucin 5AC, and Mucin 5B) are
secreted by airway mucus-secreting cells. The mucins are subject to regulation by CF
inflammatory stimuli. Mucin 5AC and Mucin 5B
have been identified as major gel-forming macromolecules; whereas
Mucin 2 contributes only to a lesser extend to the matrix
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 and Mucin 2
is weakly expressed in both cell types , , , , . 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 , , , . 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 (e.g.
Pseudomonas aeruginosa components and proinflammatory
cytokines) are known to cause mucin overproduction.
P. aeruginosa components transcriptionally upregulate
Mucin 2 gene expression , .
P. aeruginosa products have also been reported to upregulate
Mucin 5AC expression . The ultimate step
leading to Mucin 2 or Mucin 5AC
gene upregulation is the activation of several transcription factors
including Nuclear Factor kappa-B (NF-kB), Activator protein
1 (AP-1) that is
mainly composed of c-Jun and c-Fos
(c-Jun/c-Fos heterodimer), and Sp1 transcription factor
Flagellin (P. aeruginosa) and P.
aeruginosa component 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
complex in response to P. aeruginosa induces the activation
of NF-kB, initiates the proinflammatory signaling and
stimulates transcription of Mucin 2 .
TLRs activate the canonical NF-kB pathway: Myeloid
differentiation primary response gene 88 (MyD88)/
Interleukin-1 receptor-associated kinases 4, 1 and 2 (IRAK4
and IRAK1/2)/ TNF Receptor-associated factor
6 (TRAF6)/ Mitogen-activated protein kinase kinase kinase 7
interacting proteins 1 and 2 (TAB1 and
TAB2)/ Mitogen-activated protein kinase kinase kinase 7
(TAK1)/ Mitogen-activated protein kinase kinase kinase 14
(NIK)/ I-kB kinase complex
(IKK(cat))/ Nuclear factor kappa-B inhibitor
(I-kB)/ NF-kB , , . TLR2 (or TLR4) signaling
also requires an additional adaptor Toll-Interleukin 1 receptor domain containing adaptor
protein (TIRAP) , .
P. aeruginosa has also been shown to activate another
pathway: Tyrosine Kinase (c-Src)/ Harvey Rat Sarcoma Viral
Oncogene Homolog (H-Ras)/ Murine Leukemia Viral Oncogene
Homolog 1 (c-Raf-1)/ Mitogen-Activated Protein Kinase Kinase
1 and 2 (MEK1/2)/ Mitogen-Activated Protein Kinase 1 and 3
(ERK1/2)/ Ribosomal Protein S6 Kinase Alpha-1
(p90RSK1), which in turn leads to the activation of
NF-kB and triggers Mucin 2
transcription , .
Epithelial responses to CF bacterial ligands mediated by TLRs also result
in the NF-kB-induced
transcription of Interleukin 6 (IL-6)
involved in the expression of mucin genes .
Overproduction of mucin in the airways of patients with CF is also known to cause by
Epidermal Growth Factor Receptor (EGFR) activation . A prominent EGFR ligand, Transforming Growth
Factor, Alpha (TGF-alpha), is markedly increased in the
epithelium of patients with CF . EGFR
activates ERK1/2 cascade via SHC Transforming Protein
1 (Shc)/ Growth Factor
Receptor-Bound Protein 2 (GRB2)/ Son of Sevenless Homolog 1
and 2 (SOS)/
MEK1/2 pathway , leading to the activation
of c-Jun/c-Fos and SP1
transcription factors that can trigger Mucin 5AC and
Mucin 2 transcription , , .
Unlike in the case of Mucin 2 and Mucin
5AC, little is known about the mechanisms of Mucin 5B
expression. In human bronchial epithelial cell cultures,
Mucin 5B expression is activated via an
Kinase delta (PKC-delta),
H-Ras, Mitogen-Activated Protein Kinase Kinase Kinase 1
(MEKK1)-mediated, c-Jun N-terminal kinase
(JNK)/ Mitogen-Activated Protein Kinase 14
signaling pathway .
EGFR signaling could increase Mucin
5AC secretion in the airway CF epithelium, whereas Mucin 5B
production is more prominent in the lumen of patients with CF .
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