Distinct regulation of interleukin‐17 in human T helper lymphocytes

Chen, Zhi; Tato, Cristina M.; Muul, Linda; Laurence, Arian; O’Shea, John J.

doi:10.1002/art.22866

Cited by 318 publications

(302 citation statements)

References 51 publications

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“…An independent study reported that IL-1b and IL-6 induced differentiation of naïve human T cells into Th17 cells following co-stimulation with anti-CD3 and anti-CD28 in vitro [51]. These studies found that, unlike murine T cells, human naïve T cells did not differentiate into IL-17-secreting T cells in response to TGF-b and IL-6 in vitro [38,50,52,53]. Furthermore, in a study of patients with genetic traits affecting TGF-b, IL-1, IL-6 and IL-23 production, enhanced TGF-b responses, due to mutations in TGFB1 and TGFBR2, did not alter expression of Th17 cells, whereas mutations in STAT3 and IL-12RB1 impaired dedifferentiation or expansion of Th17 cells in vivo [54].…”

Section: Differentiation and Expansion Of Il-17-secreting Cd4 1 T Cellsmentioning

confidence: 99%

“…Although TGF-b is secreted by antigenspecific Treg cells, in particular Th3 cells in the gut, and induces peripheral conversion of CD4 1 CD25 À Foxp3 À T cells to CD4 1 CD25 1 Foxp3 1 Treg cells [113], this cytokine has also been shown to function with IL-6 or IL-21 to promote the differentiation of murine and human Th17 cells from naïve CD4 1 T cells in vitro [39][40][41][43][44][45]. Initial studies in humans suggested that TGF-b did not activate IL-17 production, either alone or in the presence of IL-6 [38,50,52]. However, recent studies have shown that in association with IL-21 or IL-1 and IL-23, low concentrations of TGF-b do promote human Th17 differentiation [53,55,56].…”

Section: Regulation Of Il-17-secreting T Cellsmentioning

confidence: 99%

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Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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Section: Differentiation and Expansion Of Il-17-secreting Cd4 1 T Cellsmentioning

confidence: 99%

Section: Regulation Of Il-17-secreting T Cellsmentioning

confidence: 99%

Induction, function and regulation of IL‐17‐producing T cells

2008

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“…Although Th17 cells secrete IL-17, IL-17F, IL-22 and other cytokines, its main function is the secretion of IL-17. Several cytokines are involved in the differentiation of human Th17 cells [16][17][18][19]. TGF-β and IL-6 play a key role in the Th17 differentiation, they induce CD4 + T cells differentiate to the Th17 cells by the activation of RORγt [20].…”

Section: Discussionmentioning

confidence: 99%

The role of the IL-23/IL-17 axis in the pathogenesis of Graves’ disease

Liu

2013

Endocr J

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“…IL-23-dependent Th17 cells can invade the target organ and promote the development of organ-specific autoimmune inflammation [41,42] . The current study demonstrated that DZ2002 treatment markedly reduced the Th17 population in NZB/W F 1 mice, accompanied by a comprehensive suppression of IL-17 production.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

Lin

et al. 2013

Acta Pharmacol Sin

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Aim: To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZB×NZW F1 (NZB/W F1) mice. Methods: Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg·kg -1 ·d -1 ) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study. Results: Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-β. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-β, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-κB signaling in splenocytes. DZ2002 (500 μmol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-α, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 μmol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system. Conclusion: DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.

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Distinct regulation of interleukin‐17 in human T helper lymphocytes

Cited by 318 publications

References 51 publications

Induction, function and regulation of IL‐17‐producing T cells

Induction, function and regulation of IL‐17‐producing T cells

The role of the IL-23/IL-17 axis in the pathogenesis of Graves’ disease

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

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