Chloride ion cytosol, Flagellin (P. aeruginosa), TLR2, IL-17, IL-17 receptor, Mucin 5AC, Mucin 5B, STAT3, c-Jun, IL-17F, Erk1/2, JAK2, IKK-beta, JAK2, CIKS, c-Jun, AP-1, STAT3, asialo- ganglioside GA1, IKK (cat), TLR5, TAK1, Erk1/2, TRAF6, I-kB, c-Jun/c-Fos, PilA (P. aeruginosa), None, NF-kB, ROR-gamma, Chloride ion extracellular region, IL-17RC, SP1, IL-6 receptor, IKK-gamma, IL-6, c-Jun/c-Fos, c-Fos, CFTR
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 macromolecules .
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. aeruginosa)  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 ) . 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 , .