Transcriptional Inactivation of STAT3 by PPARγ Suppresses IL-6-Responsive Multiple Myeloma Cells

Wang, Li Hua; Yang, Xiao Yi; Zhang, Xiaohu; Huang, Jiaqiang; Hou, Jian; Li, Jie; Xiong, Hong; Mihalic, Kelly; Zhu, Haoshen; Xiao, Wu; Farrar, William L.

doi:10.1016/s1074-7613(04)00030-5

Cited by 118 publications

(109 citation statements)

References 54 publications

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“…At present, it is not yet understood how Ahr interacts with Stat1 and Stat5 and negatively regulates their activation in Th17 cell differentiation. It has been reported that nuclear receptors such as peroxisome proliferator-activated receptor ␥ (PPAR␥) and estrogen receptor (ER) negatively modulate Stat3 activated by IL-6 (27). When PPAR␥ is activated by its ligand, the resultant PPAR␥-ligand complex directly interacts with IL-6-activated Stat3 and suppresses its transcriptional activity.…”

Section: Il-17 Is Produced In Cd4 ؉ Cd62l ؊ Cells Without Tgf-␤ Plus mentioning

confidence: 99%

Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells

Kimura

Naka

Nohara

et al. 2008

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

452

418

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IL-17-producing T helper cells (Th17) have been recently identified as a previously undescribed subset of helper T cells. Here, we demonstrate that aryl hydrocarbon receptor (Ahr) has an important regulatory function in the commitment of Th17 cells. Ahr was robustly induced under Th17-polarizing conditions. Ahr-deficient naïve T cells showed a considerable loss in the ability to differentiate into Th17 cells when induced by TGF-␤ plus IL-6. We were able to demonstrate that Ahr interacts with Stat1 and Stat5, which negatively regulate Th17 development. Whereas Stat1 activation returned to its basal level in Ahr wild type naïve T cells 24 h after stimulation with TGF-␤ plus IL-6, Stat1 remained activated in Ahr-deficient naïve T cells after stimulation. These results indicate that Ahr participates in Th17 cell differentiation through regulating Stat1 activation, a finding that constitutes additional mechanisms in the modulation of Th17 cell development. It has been demonstrated that these Th17 cells are associated with autoimmune conditions, such as experimental autoimmune encephalitis (EAE) and collagen-induced arthritis (CIA) (1-3). Th17 differentiation is regulated by various cytokines. Th17 differentiation was induced by TGF-␤ and IL-6 in mice, and IL-1␤ but not TGF-␤, has been shown to participate in the development of Th17 cells together with IL-6 in humans (2, 4). The development of Th17 cells is regulated negatively by IFN-␥, IL-27, and IL-2, the signals of which are dependent on Stat1 (IFN-␥ and IL-27) and Stat5 (IL-2), respectively (5-7). The orphan nuclear receptors, retinoid-related orphan receptor ␥ (ROR␥) and ROR␣, have been identified as the key transcription factors that determine the differentiation of Th17 lineage (8, 9). More recently, two groups have reported that the aryl hydrocarbon receptor (Ahr) activated by its ligand regulates Treg and Th17 cell development (10, 11). However, it is not clear how Ahr participates in the development of Th17 cells. In this paper, we demonstrate that Ahr is involved in the differentiation of Th17 cells by regulating Stat1 activation, which suppresses Th17 cell differentiation, under Th17-polarizing conditions. Ahr, also known as dioxin receptor, is a ligand-activated transcription factor that belongs to the basic-helix-loop-helix-PER-ARNT-SIM family (12,13). Ahr is present in the cytoplasm, where it forms a complex with heat shock protein (HSP) 90, Ahr-interacting protein (AIP), and p23 (14-16). Upon binding with a ligand, Ahr undergoes a conformation change, translocates to the nucleus, and dimerizes with Ahr nuclear translocator (Arnt). Within the nucleus, the Ahr/Arnt heterodimer binds to a specific sequence, designated as the xenobiotic responsive element (XRE), which causes a variety of toxicological effects (17)(18)(19)(20). Interestingly, it has been recently reported that Ahr is a ligand-dependent E3 ubiquitin ligase (21), implying that Ahr has dual functions in controlling intracellular protein levels, serving both as a transcriptional factor to prom...

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Section: Il-17 Is Produced In Cd4 ؉ Cd62l ؊ Cells Without Tgf-␤ Plus mentioning

confidence: 99%

Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells

Kimura

Naka

Nohara

et al. 2008

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

452

418

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“…In addition, PPAR␥ ligands have been shown to mediate an inhibition of IL-6 function in human multiple myeloma cells via an inhibition of STAT3 function (41,42). Therefore, ciglitazone could theoretically affect the production of or response to IL-6 in these conversion cultures.…”

Section: Ciglitazone-induced Enhancement Is Not Mediated Through Modumentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Immunoregulation: Enhancement of Regulatory T Cells through PPARγ-Dependent and -Independent Mechanisms

Wohlfert

Nichols

Nevius

et al. 2007

The Journal of Immunology

127

120

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Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism. PPARγ ligands, used to treat human type 2 diabetes, also down-regulate most immune system cells including APCs and pathogenic T cells. These effects putatively underlie the efficacy of PPARγ ligands in treating animal models of autoimmunity, leading to projections of therapeutic potential in human autoimmunity. However, the relationship between PPARγ ligands and CD4+CD25+ regulatory T cells (Tregs) has not been examined. Specifically, no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPARγ ligands, and there have been no investigations of the use of PPARγ ligands to treat autoimmunity in the absence of Tregs. We now characterize the novel relationship between ciglitazone, a thiazolidinedione class of PPARγ ligand, and both murine natural Tregs (nTregs) and inducible Tregs (iTregs). In vitro, ciglitazone significantly enhances generation of iTregs in a PPARγ-independent manner. Surprisingly, and contrary to the current paradigm, we find that, in a model of graft-vs-host disease, the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPARγ. Overall, our results indicate that, unlike its down-regulatory effect on other cells of the immune system, ciglitazone has an enhancing effect on both iTregs and nTregs, and this finding may have important implications for using PPARγ ligands in treating human autoimmune disease.

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“…Nonetheless, the mechanism by which DHEA decreases STAT3 activation remains unknown. Once again, the PPAR family of proteins could be implicated in this mechanism as it has been demonstrated that activation of PPARg, which is downregulated in PAH [83], have an inhibitory effect on STAT3 [84][85][86]. A direct physical protein-protein interaction occurs between PPARg and the active form of STAT3, resulting in a decreased transcriptional activity of STAT3.…”

Section: Dhea Anti-proliferative Propertiesmentioning

confidence: 99%

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

Paulin¹

2013

J Steroids Horm Sci

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Transcriptional Inactivation of STAT3 by PPARγ Suppresses IL-6-Responsive Multiple Myeloma Cells

Cited by 118 publications

References 54 publications

Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells

Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells

Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Immunoregulation: Enhancement of Regulatory T Cells through PPARγ-Dependent and -Independent Mechanisms

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

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