Cytokine production by Th17 cells in CF (Mouse
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 nearly 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 . In mice models, the cytokines Transforming
growth factor (TGF-beta 1) and
IL-6 have been shown to be critical for promoting Th17
differentiation , , , ,
whereas IL-23 maintains and expands the population Th17cells
, , .
Naive mouse T cells activated in the presence of TGF-beta 1
and Interleukin-2 upregulate expression of the transcription factor
Forkhead box P3 (FOXP3) and develop into T regulatory (T
reg) cells, which suppresses immune response , , , . TGF-beta 1 upregulates the
activities of the transcription factors SMAD family members 2, 3 and 4
(SMAD2, SMAD3 and
SMAD4) , and
SMAD3 can be involved in the expression of FOXP3
In contrast, murine T cells cultured with TGF-beta 1 and
IL-6 express the transcription factor Retinoic Acid
Receptor-Related Orphan Receptor Gamma-T (ROR-gamma) and
become Th17cells , , , .
The transcription factor Interferon Regulatory Factor 4
(IRF4) plays an essential role in the development of Th17
cells in mice. IRF4 can be involved in
ROR-gamma expression , .
Despite the critical function of TGF-beta 1 in the
differentiation of mouse Th17 cells, several studies indicate that this cytokine is not
needed for IL-17 production in human T cells; in fact,
TGF-beta 1 inhibits IL-17
production , , .
IL-6 acts by activating the T cell Interleukin 6 Signal
Transducer (gp130) / Janus
Kinase 2 (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 Th17 development , , . STAT3
upregulates the expression of 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 , .
IL-6 also orchestrates a series of downstream cytokine-dependent signaling pathways
that, in concert with TGF-beta 1, amplify
ROR-gamma-dependent differentiation of Th17 cells.
IL-6 induces expression of Interleukin 21
(IL-21) that amplified an autocrine loop to induce more
IL-21 in naive T cells. IL-21
and IL-23 induce the ROR-gamma,
which in synergy with STAT3 promotes
IL-17 expression , .
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 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
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 bronchial inflammatory process in CF disease
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