Vitamin A deficiency results in a priming environment conducive for Th1 cell development

Cantorna, Margherita T.; Nashold, Faye E.; Hayes, Colleen E.

doi:10.1002/eji.1830250629

Cited by 137 publications

(90 citation statements)

References 46 publications

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“…Although no specific data are available for rexinoids, some older studies with various vitamin A derivatives and retinoids hint toward multiple alternative mechanisms. These mechanisms include the modulation of immune and inflammatory responses (34,35), changes in cytokineinduced responses in macrophages (36) and smooth muscle cells (37), and altered differentiation͞proliferation of macrophages (13,15) and smooth muscle cells (38). The expression of several permissive RXR heterodimers (including PPAR and LXR) in these immune-modulatory cells does not allow us to exclude an eventual contribution of the above mechanisms in the improvement in atherosclerosis in apoE Ϫ͞Ϫ mice.…”

Section: Resultsmentioning

confidence: 99%

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Claudel

Leibowitz

Fiévet

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

273

175

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A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E ؊͞؊ mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)␥ and a dual agonist of both PPAR␣ and PPAR␥ had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXR␣ and ␤ double ؊͞؊, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR͞LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR͞LXR agonists in prevention and treatment of atherosclerosis. R etinoid X receptors (RXRs) are ubiquitously expressed nuclear receptors that heterodimerize with a number of other receptors (e.g., thyroid hormone receptor, vitamin D receptor, retinoic acid receptors, etc.; refs. 1 and 2). The elucidation of RXRs biological activity has advanced significantly through the characterization of rexinoids, high-affinity selective synthetic ligands for RXRs (1, 2). The use of rexinoids led to the demonstration that RXRs are active and permissive signaling molecules in heterodimers with the farnesol X receptor (FXR) [or bile acid receptor (BAR)], the liver X receptors (LXRs), and the peroxisome proliferatoractivated receptors (PPARs). The simultaneous activation of several permissive heterodimers underlies in part RXRs pleiotropic functions, affecting numerous receptor signaling pathways, and ranges from the control of cell proliferation, differentiation, and apoptosis (3) to the regulation of glucose and lipid metabolism (4). This pivotal role of the various permissive RXR heterodimers is in fact an emerging theme in multiple metabolic pathways. Heterodimers between RXR and PPAR␥, PPAR␣, LXR␣, and FXR͞BAR respectively inf luence glucose, triglyceride, cholesterol, and bile acid homeostasis. Dysregulation of these homeostatic control pathways can result in common metabolic disorders such as obesity, type 2 diabetes, and hyperlipidemia, which are often complicated by the development of atherosclerosis.In view of the potential implication of RXRs in various metabolic pathways implicated in atherosclerosis, we studied whether modulating the activity of these receptors or of some of their heterodimers affects the development of atherosclerosis in apolipoprotein (apo)E-deficient mice. We demonstrate here that the administration of rexinoids significantly attenuates atherosclerosis development, and we show that this effect might be linked to the activation of reverse cholesterol transpor...

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Section: Resultsmentioning

confidence: 99%

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Claudel

Leibowitz

Fiévet

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

273

175

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“…The IL-4-deficient mice used in both studies were on the same genetic background (C57BL/6), and the parasites used (Puerto Rican strain) were from the same source, so we have no specific explanation for the apparent discrepancy. However, differences in the numbers of parasites used to infect our mice, diet (42), and housing conditions could affect disease progression during infection. Regardless, the data collected from the infected IL-10/IL-4-deficient mice support the deleterious role for highly polarized type 1 cytokine responses during infection with S. mansoni.…”

Section: Discussionmentioning

confidence: 99%

IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis

Hoffmann

Cheever

Wynn

2000

The Journal of Immunology

419

374

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To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10/IL-4- and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-γ, TNF-α, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity. In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a 10-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection.

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“…Animal studies have shown that vitamin A deficiency diminishes polyclonal and Ag-specific production of Th2 cytokines (6, 10), diminishes Th2-mediated Ab responses (4,8), increases Ag-specific production of IFN-␥ (10, 26), increases IL-12 production by unstimulated lymph node cells (9), and increases anti-viral (Th1-mediated) IgG2a responses (7). In addition, in vitro treatment with RA decreases production of IL-12 by APCs and IFN-␥ by T cells and NK cells (9,39). Conversely, supplemental vitamin A increases the IgA response and production of IL-5 and IL-10 while decreasing the IgG response and production of IFN-␥ (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Vitamin A deficiency decreases the IgA, IgG1, and IgE responses but increases the IgG2a response to viral infection (6 -8). The underlying pattern of cytokine production by APCs and T cells is consistent with these effects on Ab production: vitamin A deficiency increases constitutive IL-12 production by macrophages (9), and during secondary in vitro stimulation of lymphocytes with Ag, vitamin A deficiency increases IFN-␥ production, but decreases IL-4 and IL-5 production (10). Conversely, supplemental treatment with vitamin A or retinoic acid (RA) 4 decreases IFN-␥ and increases IL-5, IL-10, and IL-4 production (11-13).…”

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confidence: 87%

Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway

Stephensen

Rasooly

Jiang

et al. 2002

The Journal of Immunology

148

108

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Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses. To identify a potential mechanism(s) underlying this in vivo activity of vitamin A, we examined the effects of all-trans and 9-cis RA on development of Th1 and Th2 cell populations using in vitro stimulation of Ag-naive Th0 cells from the DO11.10 TCR-transgenic mouse. Treatment with 9-cis, but not with all-trans RA, at primary stimulation strongly enhanced Th2 development. IL-4-neutralizing Ab blocked this activity, but IL-12- and IFN-γ-neutralizing Ab did not. Because 9-cis RA regulates gene transcription via either RA receptors or retinoid X receptors (RXRs), we tested the Th2-enhancing activities of the RXR- and RA receptor-selective agonists AGN194204 and 4-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB). AGN194204 strongly enhanced Th2 development, whereas TTNPB did not. This RXR agonist also enhanced Th2 development when purified, naive Th0 cells (L-selectinhigh/CD4+) were stimulated with CD3 and CD28 Abs in the absence of APCs. During primary antigenic stimulation of naive Th0 cells from DO11.10 mice, AGN194204 increased IL-4 and IL-5 production, decreased IFN-γ production, increased mRNA in responding T cells for genes involved in Th2 development (IL-4, GATA-3, and c-maf), and decreased mRNA for genes involved in Th1 development (IFN-γ, T-bet, and IL-12R). These data show that stimulation of the RXR pathway enhances Th2 development, perhaps by affecting the relative expression of pertinent transcription factors, cytokines, and cytokine receptors.

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Vitamin A deficiency results in a priming environment conducive for Th1 cell development

Cited by 137 publications

References 46 publications

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis

Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway

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