Cytokine production by Th17 cells in cystic
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 is caused by genetic defects in Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR) gene which encodes a chloride channel regulating
chloride transport in the lung. CFTR mutations are associated with severe lung disease
are generally found along with little to no CFTR protein expression in the membranes of
airway epithelial cells . The most common CF-causing mutation is the
homozygous deletion of a phenylalanine at amino acid position 508 (deltaF508), which
accounts for nearly 70% of defective alleles and causes 90% of disease cases , .
In the absence of normal CFTR activity, CF airways get
colonized by several bacterial species, which results in chronic stimulation of the
proinflammatory signaling. Pseudomonas aeruginosa is the
predominant pathogen of CF chronic lung infection .
The deltaF508 mutation results in misfolding and ubiquitynation which target the
protein for degradation. This leads to decreased amounts and poor functioning of
CFTR in the cell membrane resulting in inadequate chloride
transport. 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. In the absence of functional
CFTR, the height of the airway surface liquid is
significantly reduced, resulting in defective volume of ciliary movement and reduced
mucociliary clearance. This defect in mucociliary clearance results in mucus stasis and
impaired antigen clearance and potentates bacterial infection .
Epithelial response to bacterial ligands is mediated by Toll-like receptors (TLRs)
resulting in the Nuclear Factor
kappa-B (NF-kB) activation that
ultimately induces transcription of proinflammatory cytokines, including Interleukins
IL-6 and IL-8 .
These interleukins are also produced by antigen presenting cells (presumably by lung
macrophages and dendritic cells) in response to bacteria. Bacterial
lipopolysaccharides (LPS) in the presence of the LPS binding
protein (LBP) are recognized by
CD14 complex followed by NF-kB
activation. Production of Interleukin IL-23
(which is composed of two subunits, alpha (IL23A) and beta
(IL-12 beta chain)) by lung macrophages and dendritic cells
in response to mucoid P. aeruginosa is critical for the
induction of Interleukin IL-17 and the subsequent T-cell
differentiation and neutrophilic inflammation , , .
IL-17 is expressed by a distinct subset of CD4+ T helper
cells called Th17cells . IL-6 induces naive
T-cells to promote Th17 differentiation, whereas IL-23
maintains and expands the population Th17cells , , .
In mice models, in addition to IL-6, the Transforming
growth factor (TGF-beta 1) has been shown to be critical for promoting Th17
differentiation, but due to limitations of studying pure naive T-cells in humans, the
role of TGF-beta signaling in the differentiation of human naive T-cells into Th17 cells
remains unclear , , , , . Several studies indicate that TGF-beta 1
is not needed for IL-17 production in human T
cells; in fact, TGF-beta 1 inhibits
IL-17 production , , .
IL-6 induces the T cell Interleukin 6 Signal Transducer
(gp130) / Janus Kinase 1 and 2
(Jak1 and Jak 2)/ Signal
Transducer and Activator of Transcription 3 (STAT3) pathway
. Jak2/ STAT3
signaling, activated both by IL-6 and
IL-23, plays a critical role in the subsequent Th17
development , , .
STAT3 upregulates the expression of Retinoic Acid
Receptor-Related Orphan Receptor Gamma-T (ROR-gamma) , , a Th17 specific transcriptional regulator that is critical
for the expression of two members of Interleukin-17 family, IL-17A
(IL-17) and IL-17F , .
Th17cells in CF lung can signal to fibroblasts, airway epithelial cells and vascular
or/and microvascular endothelial cells .
IL-17 is a key cytokine in CF lung that regulates
granulopoiesis and neutrophil migration. IL-17 acts through
the Interleukin 17 Receptor A (IL-17 receptor) that is
associated with Interleukin 17 Receptor C (IL-17RC) to form
a multimeric receptor complex . IL-17RC
binds both IL-17F and IL-17
Little is known about the mechanisms of IL-17 receptor
signaling. After stimulation with IL-17, TRAF3 Interacting
Protein 2 (CIKS) is supposed to be recruited to
IL-17 receptor, followed by activation of E3 ubiquitin
ligase TNF Receptor-Associated Factor 6 (TRAF6) and
Mitogen-Activated Protein Kinase Kinase Kinase 7 (TAK1),
which mediates downstream activation of transcription factor
NF-kB , .
The majority of IL-17 target genes are
signaling results in the induction of IL-6, granulopoietic
growth factors, such as Granulocyte colony-stimulating factor
(G-CSF) and Granulocyte-macrophage colony-stimulating factor
(GM-CSF), chemokines, particularly Chemokine (CXC) Ligand 1
(GRO-1), Chemokine (CXC) Ligand 6
(GCP2) and IL-8, and
Intercellular Adhesion Molecule 1 (ICAM1) , . The subsequent signaling of these cytokines results in neutrophil
recruitment followed by the development of persistent bronchial inflammatory process in
CF disease .
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