Cytokine production by Th17 cells in CF (Mouse model)

Cytokine production by Th17 cells in CF (Mouse Model)

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 nearly 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]. In mice models, the cytokines Transforming growth factor (TGF-beta 1) and IL-6 have been shown to be critical for promoting Th17 differentiation [7], [8], [9], [10], whereas IL-23 maintains and expands the population Th17cells [1], [5], [11].

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 [10], [11], [12], [13]. TGF-beta 1 upregulates the activities of the transcription factors SMAD family members 2, 3 and 4 (SMAD2, SMAD3 and SMAD4) [14], and SMAD3 can be involved in the expression of FOXP3 [15].

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 [11], [13], [14], [16]. 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 [11], [17].

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 [11], [18], [19].

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 [20]. Jak2 / STAT3 signaling, activated both by IL-6 and IL-23, plays a critical role in Th17 development [21], [22], [23]. STAT3 upregulates the expression of ROR-gamma [11], [24], 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 [16], [25].

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 [26], [27].

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 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 [28]. IL-17RC binds both IL-17F and IL-17 [29].

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 [30], [31]. 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 bronchial inflammatory process in CF disease [1].

References:

1. 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
2. Rowe SM, Miller S, Sorscher EJ
   Cystic fibrosis. The New England journal of medicine 2005 May 12;352(19):1992-2001
3. Gomez MI, Prince A
   Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis. Current opinion in pharmacology 2007 Jun;7(3):244-51
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. Stockinger B, Veldhoen M, Martin B
    Th17 T cells: linking innate and adaptive immunity. Seminars in immunology 2007 Dec;19(6):353-61
11. Laurence A, O'Shea JJ
    T(H)-17 differentiation: of mice and men. Nature immunology 2007 Sep;8(9):903-5
12. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM
    Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. The Journal of experimental medicine 2003 Dec 15;198(12):1875-86
13. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H
    Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science (New York, N.Y.) 2007 Jul 13;317(5835):256-60
14. Weaver CT, Hatton RD, Mangan PR, Harrington LE
    IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annual review of immunology 2007;25:821-52
15. Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M
    Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nature immunology 2008 Feb;9(2):194-202
16. 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
17. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M
    The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nature immunology 2007 Sep;8(9):958-66
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR
    IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature immunology 2007 Sep;8(9):967-74
27. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK
    IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007 Jul 26;448(7152):484-7
28. 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
29. 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
30. 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
31. 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