Cutting Edge: Inhibition of the Retinoid X Receptor (RXR) Blocks T Helper 2 Differentiation and Prevents Allergic Lung Inflammation

Grenningloh, Roland; Gho, Andrea; Lucia, Pietro Di; Klaus, Michael; Bollag, W.; Ho, I‐Cheng; Sinigaglia, Francesco; Panina-Bordignon, Paola

doi:10.4049/jimmunol.176.9.5161

Cited by 30 publications

(28 citation statements)

References 19 publications

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“…The active metabolite of vitamin A, retinoic acid, acts to regulate gene transcription via two families of nuclear receptors, the retinoic acid receptor (RAR-␣, -␤, -␥) and the retinoid X receptor (RXR-␣, -␤, -␥) (8). In agreement with the data from dietary studies, disruption of the Rxr␣ gene can produce a Th1 bias (9,10) and treatment of mice with a retinoid X receptor antagonist can decrease Th2-mediated pulmonary eosinophilic inflammation (11).…”

supporting

confidence: 85%

Vitamin A Deficiency Decreases and High Dietary Vitamin A Increases Disease Severity in the Mouse Model of Asthma

Schuster

Kenyon

Stephensen

2008

The Journal of Immunology

105

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The Th1/Th2 paradigm has become an important issue in the pathogenesis of asthma, characterized by normal Th1 and elevated Th2 cytokine expression. Vitamin A deficiency (VAD) can produce a Th1 bias, whereas high-level dietary vitamin A can promote a Th2 bias. We used the OVA exposure mouse model to determine the contributions of vitamin A-deficient, control (4IU/g), and high-level vitamin A (250-IU/g) diets to the development of allergic airway inflammation and hyperresponsiveness. VAD reduced serum IgE and IgG1 responses, pulmonary eosinophilia, and the levels of IL-4 and IL-5 in bronchoalveolar lavage specimens, whereas the 250-IU/g diet increased serum IgE. Also, VAD blocked pulmonary hyperresponsiveness following methacholine challenge while the 250-IU/g diet exacerbated pulmonary hyperresponsiveness. In conclusion, VAD diminished and high-level dietary vitamin A enhanced the development of experimental asthma in this model system. These data suggest that excessive intake of vitamin A may increase the risk or severity of asthma in industrialized countries whereas vitamin A deficiency continues to increase mortality from infectious diseases in developing countries.

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supporting

confidence: 85%

Vitamin A Deficiency Decreases and High Dietary Vitamin A Increases Disease Severity in the Mouse Model of Asthma

Schuster

Kenyon

Stephensen

2008

The Journal of Immunology

105

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“…Consistent with the reports of other groups, we found that Th2 cells preferentially express high levels of RXR␣. 31 However, we also found that Th17 cells were distinct in expressing high levels of RAR␣ and RAR␥. In addition, Th17 cells also express high levels of the orphan receptor ROR␥t, which was downregulated by ATRA ( Figure 3C).…”

mentioning

confidence: 61%

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Elias

Laurence

Davidson

et al. 2008

Blood

396

333

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IntroductionImmune responses are orchestrated by subsets of CD4 ϩ helper and effector T cells. Classically, differentiated T cells have been classified as belonging either to T-helper 1 (Th1) or Th2 lineages. 1 Th1 cells secrete interferon-gamma (IFN-␥) in response to interleukin-12 (IL-12) and require the transcription factors T-box21 (T-bet) and signal transducer and activator of transcription 4 (Stat4) 2 and Stat1, whereas Th2 cells secrete IL-4, IL-5, and IL-13 and require the transcription factors GATA-binding protein 3 (GATA-3) and Stat6. 3 While this simple paradigm was instrumental in understanding immune responses to model pathogens, it was less clear how such a model explained the pathogenesis of autoimmune disease.More recently, additional fates for CD4 ϩ T cells have emerged that provide more insights into the mechanisms of tolerance and immune-mediated disease. One of these new subsets of T cells, expressing the transcription factor FoxP3, is termed regulatory T cells (Tregs) and serves to inhibit immune responses. Deficiency of FoxP3 in mice and humans is associated with fatal autoimmune disease. 4,5 FoxP3 ϩ Tregs normally develop in the thymus, but FoxP3 expression and Treg function also develop when naive CD4 ϩ T cells are stimulated in vitro with transforming growth factor-␤1 (TGF-␤1) and IL-2. 6 Development and differentiation of Tregs and expression of FoxP3 are dependent upon another transcription factor, Stat5. 7,8 Another new subset of T cells that may be related to Tregs is a subset that produces the proinflammatory cytokine IL-17 (Th17 cells). Overproduction of IL-17 has been noted in a variety of models of autoimmune disease, including experimental autoimmune encephalomyelitis and collagen-induced arthritis. 9-13 Importantly, increased levels of IL-17 are also seen in human diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. 14-16 Th17 cells are generated by the cytokines TGF-␤1 and IL-6, the latter of which acts via Stat3 to induce the transcription factor retinoic acid orphan receptor gamma (ROR␥t). 17 Overexpression of ROR␥t induces IL-17 production, whereas deficiency of this transcription factor virtually abrogates Th17 differentiation.ROR␥t belongs to a superfamily of retinoid nuclear receptors that include the retinoic acid receptors (RARs), retinoid X receptors (RXRs), and other RORs. 18 A connection between retinoids and CD4 ϩ T-cell differentiation has long been recognized. Memory T cells from vitamin A-deficient mice have been found to overproduce . 19 In contrast, administration of the active metabolite of vitamin A, retinoic acid (RA), has been reported to suppress memory cell IFN-␥ production and increase IL-4 secretion. 20 Later, it emerged that vitamin A can be metabolized into retinoic acid isomers with different ligand-receptor affinities: 9-cis retinoic acid, with a higher affinity for the RXR family, and all-trans retinoic acid (ATRA), with a higher affinity for the RAR family. 21 Acting through RXR␣, 9-cis retinoic acid skews n...

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“…Acta Pharmacologica Sinica npg production in T cells [89] . Thus, the diverse anti-inflammatory effects of RXRα and its ligands in various cell types underscore their function in the prevention and treatment of inflammatory and metabolic disorders, such as cancer, atherosclerosis, insulin resistance, autoimmunity, and neurodegeneration.…”

Section: Wwwchinapharcom Zhang Xk Et Almentioning

confidence: 99%

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/ AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.

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Cutting Edge: Inhibition of the Retinoid X Receptor (RXR) Blocks T Helper 2 Differentiation and Prevents Allergic Lung Inflammation

Cited by 30 publications

References 19 publications

Vitamin A Deficiency Decreases and High Dietary Vitamin A Increases Disease Severity in the Mouse Model of Asthma

Vitamin A Deficiency Decreases and High Dietary Vitamin A Increases Disease Severity in the Mouse Model of Asthma

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

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