Chang, S. H. & Dong, C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res. 17, 435-440

Department of Immunology, MD Anderson Cancer Center, 7455 Fannin, Unit 906, Houston, TX 77030, USA.
Cell Research (Impact Factor: 12.41). 06/2007; 17(5):435-40. DOI: 10.1038/cr.2007.35
Source: PubMed


CD4+ helper T (TH) cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed TH(IL-17), TH17 or inflammatory TH (THi), has been identified as critical mediators of tissue inflammation. These cells produce IL-17 (also called IL-17A) and IL-17F, two most homologous cytokines sharing similar regulations. Here we report that when overexpressed in 293T cells, IL-17 and IL-17F form not only homodimers but also heterodimers, which we name as IL-17A/F. Fully differentiated mouse THi cells also naturally secrete IL-17A/F as well as IL-17 and IL-17F homodimeric cytokines. Recombinant IL-17A/F protein exhibits intermediate levels of potency in inducing IL-6 and KC (CXCL1) as compared to homodimeric cytokines. IL-17A/F regulation of IL-6 and KC expression is dependent on IL-17RA and TRAF6. Thus, IL-17A/F cytokine represents another mechanism whereby T cells regulate inflammatory responses and may serve as a novel target for treating various immune-mediated diseases.

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    • "IL-17 (or IL-17A) is the founding member of a family of six structurally related cytokines named IL-17A through F (Aggarwal and Gurney, 2002; Weaver et al., 2007). The most closely related IL-17 members, IL-17A and IL-17F, can be secreted as IL-17A/A and IL-17F/F homodimers as well as an IL-17A/F heterodimer (Chang and Dong, 2007). All three are produced by Th17 cells but, arguably, IL-17A/A and IL-17A/F are the more proinflammatory members (Ishigame et al., 2009). "
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    ABSTRACT: Therapies targeting either interleukin-23 (IL-23) or interleukin-17 (IL-17) have shown promise in treating Th17-driven autoimmune diseases. Although IL-23 is a critical driver of IL-17, recognition of non-redundant and independent functions of IL-23 and IL-17 has prompted the notion that dual inhibition of both IL-23 and IL-17 could offer even greater efficacy for treating autoimmune diseases relative to targeting either cytokine alone. To test this hypothesis, we generated selective inhibitors of IL-23 and IL-17 and tested the effect of either treatment alone compared with their combination in vitro and in vivo. In vitro, using a novel culture system of murine Th17 cells and NIH/3T3 fibroblasts, we showed that inhibition of both IL-23 and IL-17 completely suppressed IL-23-dependent IL-22 production from Th17 cells and cooperatively blocked IL-17 dependent IL-6 secretion from the NIH/3T3 cells to levels below either inhibitor alone. In vivo, in the imiquimod (IMQ) induced skin inflammation model, and in the MOG peptide-induced experimental autoimmune encephalomyelitis (EAE) model, we demonstrated that dual inhibition of IL-17 and IL-23 was more efficacious in reducing disease than targeting either cytokine alone. Together, these data support the hypothesis that neutralization of both IL-23 and IL-17 may provide enhanced benefit against Th17 mediated autoimmunity and provide a basis for a therapeutic strategy aimed at dual targeting IL-23 and IL-17. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · May 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "Cytokines that belong to the Th17 response such as IL-23A, IL-17F and IL-22 were negatively correlated with TDGs and pocket depth. The effect of IL-17F and IL-22 in activation of MMPs and osteoclastogenesis has not been well described; however these cytokines appear to play important roles in the maintenance of mucosal barrier homeostasis and regulation of inflammation (Chang and Dong, 2007, Sonnenberg et al., 2011). As an example, IL-23p19 inhibits osteoclastogenesis by inducing GM-CSF production by Th17 and γδ T cells (Quinn et al., 2008). "
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    ABSTRACT: Aim: Variations in the expression of cytokines during the progression of periodontitis remain ill-defined. We evaluated the expression of 19 cytokine genes related to T-cell phenotype/function during initiation, progression and resolution of periodontitis, and related these to the expression of soft and bone tissue destruction genes (TDGs). Materials and methods: A ligature-induced periodontitis model was used in rhesus monkeys (M. mulatta) (n = 18). Gingival tissues were taken at baseline pre-ligation, 2 weeks and 1 month (Initiation) and 3 months (progression) post ligation. Ligatures were removed and samples taken 2 months later (resolution). Total RNA was isolated and the Rhesus Gene 1.0 ST (Affymetrix) used for gene expression analysis. Significant expression changes were validated by qRT-PCR. Results: Disease initiation/progression was characterized by overexpression of Th17/Treg cytokine genes (IL-1β, IL-6, TGFβ and IL-21) and down-regulation of Th1/Th2 cytokine genes (IL-18 and IL-25). Increased IL-2 and decreased IL-10 levels were seen during disease resolution. Several Th17/Treg cytokine genes positively correlated with TDGs, whereas most Th1/Th2 genes exhibited a negative correlation. Conclusion: Initiation, progression and resolution of periodontitis involve over- and underexpression of cytokine genes related to various T-helper subsets. In addition, variations in individual T-helper response subset/genes during disease progression correlated with protective/destructive outcomes.
    Full-text · Article · Jun 2014 · Journal Of Clinical Periodontology
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    • "Even though TNF and IL-10 are thought to contribute to the degree of anaemia in children with falciparum malaria, no significant difference was observed among the mice strains in this study, and even when compared with uninfected control. IL-17 promotes inflammation [28] by activating cells to produce more pro-inflammatory cytokines and also thought to be associated with autoimmunity [29] suggesting that these phenomena may be associated more with Balb/c. "
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    ABSTRACT: Malaria anaemia is still a major public health problem and its pathogenesis still unclear. Interestingly, the progression of anaemia is at relatively low parasitaemia with some mortality in the semi-immune individuals in the endemic areas despite adequate erythropoietin (EPO) synthesis. A recent study has shown that treatment with exogenous anti-erythropoietin (anti-EPO) antibodies (Ab) of infected mice gives protection against malaria infection, suggesting an important role for anti-EPO Ab in malaria. The objective of the study was to evaluate anti-EPO antibody levels in anaemic condition of different strains of semi-immune mice with malaria.MethodologySemi-immune status was attained in four mice strains (Balb/c, B6, CBA and NZW) by repeated infections with 104 Plasmodium berghei ANKA, and treatment with chloroquine/pyrimethamine. ELISA was used to measure anti-EPO Ab, transferrin and EPO while inflammatory cytokines measurement was done using bead-based multiplex assay kit. The mean anti-EPO Ab levels in the mice strains [Optical Density (OD) values at 450 nm: Balb/c (2.1); B6 (1.3); CBA (1.4) and NZW (1.7)] differed (p = 0.045), and were significantly higher when compared with uninfected controls, p < 0.0001, and mean anti-EPO Ab levels in the mice strains at recovery [OD values at 450 nm: Balb/c (1.8); B6 (1.1); CBA (1.5) and NZW (1.0) also differed (p = 0.0004). Interestingly, EPO levels were significantly high in NZW and low in Balb/c mice (p < 0.05), with those of B6 and CBA of intermediary values. Again, NZW were highly parasitaemic (20.7%) and the other strains (Balb/c, B6 and CBA) ranged between 2.2-2.8% (p = 0.015). Anti-EPO Ab correlated positively with extent of Hb loss (r = 0.5861; p = 0.003). Correlation of anti-EPO antibody with EPO was significant only in Balb/c mice (r = -0.83; p = 0.01). Significant levels of IL6 and IFNgamma (p < 0.0001), both known to be associated with erythropoiesis suppression were observed in the Balb/c. Transferrin was significantly lower in Balb/c (p < 0.0001) when compared with the other mice strains (B6, CBA and NZW). This is the first ever report in estimating endogenous anti-EPO antibodies in malaria anaemia. The data presented here suggest that anti-EPO Ab is produced at infection and is associated with Hb loss. Host factors appear to influence anti-EPO antibody levels in the different strains of mice.
    Full-text · Article · Aug 2013 · Malaria Journal
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