Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses (original) (raw)
Related papers
Modern Rheumatology, 2010
Retinoids are known to promote T helper (Th)2 and regulatory T cell (Treg) differentiation, and suppress Th1 and Th17 in vitro. Am80, a synthetic retinoid, is reported to ameliorate collagen-induced arthritis (CIA). The aims of this study are to determine the effects of Am80 on CIA in detail, and on Th development and antibody (Ab) production in vivo. Murine CIA was induced by immunization with bovine type II collagen (CII) at days 1 and 22. Treatment with Am80 from day 1 to 35 significantly lowered clinical arthritis score, suppressed cellular infiltration and bone destruction in the joint, decreased interleukin (IL)-17 and increased interferon (IFN)-c production by CII-stimulated splenocytes, and decreased proportion of Foxp3 ? splenic CD4 T cells and serum anti-CII Ab levels. Thus, Am80 inhibited Th17 and Treg and enhanced Th1 differentiation in vivo. In contrast, Am80 applied from day 15 to 35 did not alter arthritis score, IL-17 or IFN-c production by CII-stimulated splenocytes, but decreased the proportion of Foxp3 ? splenic CD4 T cells and serum anti-CII Ab levels. Am80 exhibits inhibitory effects on CIA and might regulate both Th development and Ab production in vivo. Decreased Th17 by treatment with Am80 might be responsible for the attenuation of arthritis.
Arthritis & Rheumatism, 2009
Objective. Polymyositis and dermatomyositis are chronic inflammatory muscle diseases. Retinoids are compounds that bind to the retinoic acid binding site of retinoic acid receptors and have biologic activities similar to those of vitamin A. Recent studies indicate that retinoids promote Th2 differentiation and suppress Th1 and Th17 differentiation in vitro. The present study was undertaken to examine the effects of a synthetic retinoid, Am80, on experimental autoimmune myositis as well as on Th phenotype development and antibody production. Methods. Experimental autoimmune myositis was induced in SJL/J mice by immunization with rabbit myosin. Am80 was administered orally once daily. Its effects were evaluated by measurement of the numbers of infiltrating inflammatory cells, production of inflammatory cytokines in muscle, production of Th-specific cytokines by myosin-stimulated splenic T cells, and production of antimyosin antibodies in serum. Results. In mice with experimental autoimmune myositis, orally administered Am80 significantly reduced the number of infiltrating inflammatory cells and the expression of tumor necrosis factor ␣ and interleukin-1 (IL-1) in muscle. Moreover, Am80 increased production of interferon-␥, IL-4, and IL-10, but not IL-17, by myosin-stimulated splenic T cells of mice with experimental autoimmune myositis, suggesting that it could enhance differentiation into Th1 and Th2, but not Th17, in vivo. Am80 also decreased serum levels of IgG2a and IgG2b antimyosin antibodies, but did not affect levels of IgG1 antimyosin antibodies. In addition, it suppressed chemokine expression and activator protein 1 activity in myoblasts in vitro. Conclusion. The synthetic retinoid Am80 has an inhibitory effect on experimental autoimmune myositis. It might regulate the development of Th phenotype and antibody production in vivo, in addition to its effects on cytokine and chemokine production.
Are Th17 Cells an Appropriate New Target in the Treatment of Rheumatoid Arthritis?
Clinical and Translational Science, 2010
Discovery of Th 17 cells Until about a decade ago, many human autoimmune diseases and the corresponding experimental animal models had been viewed as being driven by Th 1 cells. However, immunologists encountered a dilemma when they realized that experimental autoimmune encephalomyelitis (EAE: a mouse model of multiple sclerosis) and collagen-induced arthritis (CIA: a mouse model of rheumatoid arthritis) both were aggravated by the absence of Th 1 associated cytokines, receptors or transcription factors, such as IFN-γ, IFN-γ receptor, IL-12 p35, IL-12 receptor  2, or Stat1. 1-5 However, mice lacking the IL-12p40 subunit, which is found not only in IL-12 but also in IL-23, were resistant to these diseases, and IL-23p19 knockout mice were shown to be protected from EAE 6 and CIA. 7 Th is paradox was resolved in 2005 by a discovery of new subset of CD4+ T cells that produce IL-17A and IL-17F, expand in response to IL-23, and induce EAE and CIA upon adoptive transfer in mice. 8-10 Th ese lymphocytes, termed Th 17 cells, are characterized by expression of RORγt as a master regulator gene as well as secretion of IL-17A, IL-17F, IL-21, and IL-22. Th 17 cells are crucial in host defense against extracellular bacteria and some fungi, which Th 1 and Th 2 immunity are not fully eff ective against, and also play essential roles in many autoimmune or infl ammatory diseases, both in mice and humans (Table 1). 11-13 Discussion What is the connection between Th 17 cells and rheumatoid arthritis? Multiple lines of evidence indicate that Th 17 cells are important in rheumatoid arthritis (RA). As summarized in Table 2 , IL-17 activates a diverse array of cell types that participate in the pathogenesis of RA, including synovial fi broblasts, monocytes, macrophages, chondrocytes, and osteoblasts. IL-17 induces production of proinfl ammatory cytokines, such as TNF, IL-1, IL-6, IL-23, which amplify positive feedback loops that commit naïve CD4 T cells to the Th 17 lineage. 14-16 By inducing chemokine production, IL-17 indirectly attracts numerous eff ector T cells, B cells, monocytes, and neutrophils to the infl amed joint. 17 Of note, acting in synergy with TNF and IL-1-β, IL-17 induces CCL20, 18 which strongly attracts lymphocytes, including Th 17 cells that express CCR6, a receptor for CCL20. In bone, IL-17 stimulates osteoblasts to express receptor activator of nuclear factor kappa-B ligand (RANKL). 19 Such osteoblasts then activate osteoclasts that express RANK as a membrane receptor. Th is interaction leads to bone resorption. Finally, induction of matrix metalloproteinases (MMPs) 20 and vascular endothelial growth factor (VEGF) 21 are crucial in tissue destruction and angiogenesis, respectively. Brief overview of Th 17 diff erentiation in mice In mice, the combination of TGF-β and IL-6 or IL-21 induces Th 17 cells. 22-24 IL-6 or IL-21 phosphorylates Stat3, which induces RORγt expression. 25 Stat3 and RORγt appear to cooperate with each other 26 and bind to the IL-17 promoter to induce IL-17 expression. 27,28 TGF-β induces not only RORγt but also FoxP3 (master regulator gene of regulatory T cells: Tregs), 23,29,30 which physically associates with RORγt as well as Runx1. 28,29 In the absence of proinfl ammatory cytokines, FoxP3, through interaction with Runx1, inhibits RORγt-directed IL-17 expression, which is crucial in maintaining homeostasis of the immune network through generation of Tregs. 28,29 However, in the presence of proinfl ammatory cytokines, Stat3 and IRF4 both play essential roles in IL-6/21-and IL-6-mediated down-regulation of FoxP3, respectively, 31,32 aft er which RORγt primarily cooperates with Runx1 to induce IL-17. 28 In this manner, IL-6 or IL-21 play a pivotal role in tipping the balance toward Th 17, but not Treg diff erentiation by inhibiting TGF-β−mediated FoxP3 expression. 23,29 IL-21 produced by Th 17 cells in the presence of TGF-β induces Th 17 cells, creating an autoamplifi cation loop for Th 17 diff erentiation. 26,33,34 Th us, IL-21 might play a crucial role in maintaining a precursor pool of Th 17 cells when the supply of IL-6 is limited. Both IL-6 and IL-21, in cooperation with TGF-β, induce expression of the IL-23 receptor in a Stat3-26 and RORγt-dependent 33 fashion. Stat4, which has been viewed to be primarily essential for IL-12 signaling for Th 1 lineage commitment, was shown to also be important for IL-23-mediated expression of IL-17 in CD4 T cells in vitro. 35
Mediators of Inflammation, 2015
In recent years several studies investigated the role of T lymphocyte subpopulations in the pathogenesis of rheumatoid arthritis (RA). Pathogenic Th17 cells mediate pannus growth, osteoclastogenesis, and synovial neoangiogenesis; hence they are key players in the development of the disease. On the other hand, regulatory T (Treg) cells are a T cell subset whose peculiar function is to suppress autoreactive lymphocytes. The imbalance between Th17 and Treg cells has been identified as a crucial event in the pathogenesis of RA. In addition, the effects of currently employed RA therapeutic strategies on these lymphocyte subpopulations have been extensively investigated. This review article aims to discuss current knowledge on Treg and Th17 cells in RA and possible implications of their therapeutic targeting in this disorder.
BMC Immunology, 2008
We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cisretinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-γ and TNF-α expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-α (RAR-α)-selective agonist, AM580 but not with the RAR-β/γ ligand, 4-hydroxyphenylretinamide (4-HPR).
Gastroenterology, 2009
IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RAR␣, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RAR␣ or LE135 as the antagonist of RAR␣. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and downregulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-␣, IL-1, IL-17) but more regulatory cytokines (IL-10, TGF-) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment. J. Leukoc. Biol. 86: 000 -000; 2009.
AJP: Lung Cellular and Molecular Physiology, 2003
Retinoic acid (RA) is known to accelerate wound healing and induce cell differentiation. All-trans-RA (ATRA) exerts its effect by binding retinoic acid receptors (RARs), members of the nuclear receptor family. We investigated whether RA can alter expression of eotaxin, a potent eosinophil chemoattractant which is regulated by the transcription factors, signal transducer and activator of transcription 6 (STAT6) and nuclear factor-κB. We examined the effects of RA on eotaxin expression in a human bronchial epithelial cell line BEAS-2B. ATRA and its stereodimer 9-cis retinoic acid (9-cis RA) inhibited interleukin-4 (IL-4)-induced release of eotaxin at 10 -6 M by 78.0% and 52.0%, respectively (P<0.05). ATRA and 9-cis RA also significantly inhibited IL-4-induced eotaxin mRNA expression at 10 -6 M by 52.3% and 53.5%, respectively (P<0.05). In contrast, neither ATRA nor 9-cis RA had any effects on tumor necrosis factor-α-induced eotaxin production.
Retinoic Acid Can Exacerbate T Cell Intrinsic TLR2 Activation to Promote Tolerance
PloS one, 2015
The contribution of vitamin A to immune health has been well established. However, recent evidence indicates that its active metabolite, retinoic acid (RA), has the ability to promote both tolerogenic and inflammatory responses. While the outcome of RA-mediated immunity is dependent upon the immunological status of the tissue, the contribution of specific innate signals influencing this response have yet to be delineated. Here, we found that treatment with RA can dampen inflammation during intestinal injury. Importantly, we report a novel and unexpected requirement for TLR2 in RA-mediated suppression. Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells. These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease.
Th17 development and autoimmune arthritis in the absence of reactive oxygen species
European Journal of Immunology, 2008
Dendritic cells (DC) express a functional NADPH oxidase and produce reactive oxygen species (ROS) upon interaction with microbes and T cells. Exposure to ROS leads to DC activation and maturation, as evidenced by phenotypic and functional changes. We have evaluated how endogenous ROS production affects the cytokine secretion pattern and T cell-activating capacity of bone marrow-derived murine DC. DC treated with ROS scavengers, as well as DC from mice that lack a functional NADPH oxidase (and thereby inherently deficient in ROS production) produced significantly increased levels of IL-1b, IL-6, TNF-a and TGF-b in response to microbial activation. DC deficient in ROS production induced high levels of IFN-c and IL-17 in responding T cells after Ag-specific or superantigen-induced activation. Finally, we show that ROS deficiency affected the induction of a T cell-dependent inflammatory condition, collagen-induced arthritis (CIA). C57BL/6 mice that lack a functional NADPH oxidase developed a severe and erosive CD4dependent CIA, whereas the majority of the congenic wild-type animals remained healthy. These data suggest that ROS act as immunomodulators in DC-driven T cell activation and perhaps also in T cell-dependent immunopathology.