Cytokine production by Th17 cells in cystic
fibrosis
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 [1].
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 [2]. 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 [1], [2].
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 [3].
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 [1].
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 [3].
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
TLR4/ MD-2/
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 [1], [4], [5].
IL-17 is expressed by a distinct subset of CD4+ T helper
cells called Th17cells [6]. IL-6 induces naive
T-cells to promote Th17 differentiation, whereas IL-23
maintains and expands the population Th17cells [1], [5], [7].
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 [7], [8], [9], [10], [11]. 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 [7], [12], [13].
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
[14]. Jak2/ STAT3
signaling, activated both by IL-6 and
IL-23, plays a critical role in the subsequent Th17
development [15], [16], [17].
STAT3 upregulates the expression of Retinoic Acid
Receptor-Related Orphan Receptor Gamma-T (ROR-gamma) [7], [18], 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 [19], [20].
Th17cells in CF lung can signal to fibroblasts, airway epithelial cells and vascular
or/and microvascular endothelial cells [1].
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 [21]. IL-17RC
binds both IL-17F and IL-17
[22].
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 [23], [24].
The majority of IL-17 target genes are
NF-kB-dependent. IL-17
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) [1], [5]. The subsequent signaling of these cytokines results in neutrophil
recruitment followed by the development of persistent bronchial inflammatory process in
CF disease [1].
References:
- Dubin PJ, McAllister F, Kolls JK
Is cystic fibrosis a TH17 disease?
Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
- Rowe SM, Miller S, Sorscher EJ
Cystic fibrosis.
The New England journal of medicine 2005 May 12;352(19):1992-2001
- Gomez MI, Prince A
Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis.
Current opinion in pharmacology 2007 Jun;7(3):244-51
- Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
The Journal of experimental medicine 2005 Jan 17;201(2):233-40
- McAllister F, Henry A, Kreindler JL, Dubin PJ, Ulrich L, Steele C, Finder JD, Pilewski JM, Carreno BM, Goldman SJ, Pirhonen J, Kolls JK
Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis.
Journal of immunology (Baltimore, Md. : 1950) 2005 Jul 1;175(1):404-12
- Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
Nature immunology 2005 Nov;6(11):1133-41
- Laurence A, O'Shea JJ
T(H)-17 differentiation: of mice and men.
Nature immunology 2007 Sep;8(9):903-5
- Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
Immunity 2006 Feb;24(2):179-89
- Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT
Transforming growth factor-beta induces development of the T(H)17 lineage.
Nature 2006 May 11;441(7090):231-4
- Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
Nature 2006 May 11;441(7090):235-8
- Stockinger B, Veldhoen M, Martin B
Th17 T cells: linking innate and adaptive immunity.
Seminars in immunology 2007 Dec;19(6):353-61
- Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R
Development, cytokine profile and function of human interleukin 17-producing helper T cells.
Nature immunology 2007 Sep;8(9):950-7
- Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F
Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
Nature immunology 2007 Sep;8(9):942-9
- Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F, Aono H, Ishihara K, Huseby E, Betz UA, Murakami M, Hirano T
IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state.
International immunology 2007 Jun;19(6):695-702
- Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW
A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 1;168(11):5699-708
- Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY
STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice.
Journal of immunology (Baltimore, Md. : 1950) 2006 May 1;176(9):5652-61
- Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, Hipkiss EL, Getnet D, Goldberg MV, Maris CH, Housseau F, Yu H, Pardoll DM, Drake CG
Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity.
Journal of immunology (Baltimore, Md. : 1950) 2007 Oct 1;179(7):4313-7
- Kimura A, Naka T, Kishimoto T
IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells.
Proceedings of the National Academy of Sciences of the United States of America 2007 Jul 17;104(29):12099-104
- Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR
The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
Cell 2006 Sep 22;126(6):1121-33
- Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C
STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.
The Journal of biological chemistry 2007 Mar 30;282(13):9358-63
- Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J
Cutting edge: interleukin 17 signals through a heteromeric receptor complex.
Journal of immunology (Baltimore, Md. : 1950) 2006 Jul 1;177(1):36-9
- Kuestner RE, Taft DW, Haran A, Brandt CS, Brender T, Lum K, Harder B, Okada S, Ostrander CD, Kreindler JL, Aujla SJ, Reardon B, Moore M, Shea P, Schreckhise R, Bukowski TR, Presnell S, Guerra-Lewis P, Parrish-Novak J, Ellsworth JL, Jaspers S, Lewis KE, Appleby M, Kolls JK, Rixon M, West JW, Gao Z, Levin SD
Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.
Journal of immunology (Baltimore, Md. : 1950) 2007 Oct 15;179(8):5462-73
- Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, Xiao J, Lu Y, Giltiay N, Liu J, Kordula T, Zhang QW, Vallance B, Swaidani S, Aronica M, Tuohy VK, Hamilton T, Li X
The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.
Nature immunology 2007 Mar;8(3):247-56
- Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D, Gaffen SL
Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression.
Proceedings of the National Academy of Sciences of the United States of America 2007 May 1;104(18):7506-11