Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines

Doi, Yoshimitsu; Oki, Sadaaki; Ozawa, Tomoko; Hohjoh, Hirohiko; Miyake, Sachiko; Yamamura, Takashi

doi:10.1073/pnas.0803454105

Cited by 81 publications

(70 citation statements)

References 41 publications

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“…NR4A2 was previously shown to have an important role in brain in normal dopamine cell functions (50) in the regulation of osteopontin in osteoblasts (51) and in the regulation of key cytokines in T cells (52). In AOK-B50 cells PTH induces NF4A2, and C/EBP␤ was found to inhibit the NF4A2 induction of 1␣(OH)ase transcription (8).…”

Section: Discussionmentioning

confidence: 97%

Calcitonin, a Regulator of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene

Zhong

Armbrecht

Christakos

2009

Journal of Biological Chemistry

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Although parathyroid hormone (PTH) induces 25-hydroxyvitamin D 3 (25(OH)D 3 ) 1␣-hydroxylase (1␣(OH)ase) underhypocalcemic conditions, previous studies showed that calcitonin, not PTH, has an important role in the maintenance of serum 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) under normocalcemic conditions. In this study we report that 1␣(OH)ase transcription is strongly induced by calcitonin in kidney cells and indicate mechanisms that underlie this regulation. The transcription factor C/EBP␤ is up-regulated by calcitonin in kidney cells and results in a significant enhancement of calcitonin induction of 1␣(OH)ase transcription and protein expression. Mutation constructs of the 1␣(OH)ase promoter demonstrate the importance of the C/EBP␤ binding site at ؊79/؊73 for activation of the 1␣(OH)ase promoter by calcitonin. The SWI/SNF chromatin remodeling complex was found to cooperate with calcitonin in the regulation of 1␣(OH)ase. Chromatin immunoprecipitation analysis showed that calcitonin recruits C/EBP␤ to the 1␣(OH)ase promoter, and Re-chromatin immunoprecipitation analysis (sequential chromatin immunoprecipitations using different antibodies) showed that C/EBP␤ and BRG1, an ATPase that is a component of the SWI/SNF complex, bind simultaneously to the 1␣(OH)ase promoter. These findings are the first to address the dynamics between calcitonin, C/EBP␤, and SWI/SNF in the regulation of 1␣(OH)ase and provide a mechanism, for the first time, for calcitonin induction of 1␣(OH)ase. Because plasma calcitonin as well as 1,25(OH) 2 D 3 have been reported to be increased during pregnancy and lactation and in early development, these findings suggest a mechanism that may account, at least in part, for the increase in plasma 1,25(OH) 2 D 3 during these times of increased calcium requirement.Vitamin D is a principal factor required for maintaining normal calcium homeostasis (1). The active form of vitamin D,3 is generated by two successive hydroxylations; 25-hydroxylation in the liver and 1␣-hydroxylation in the kidney (1-3). Inactivating mutations in the 25-hydroxvitamin D 3 1␣-hydroxylase (1␣(OH)ase) gene result in vitamin D dependent rickets type I despite normal intake of vitamin D, indicating the importance of the 1␣(OH)ase enzyme (4, 5). Elevated parathyroid hormone (PTH) resulting from hypocalcemia is a primary signal mediating the renal synthesis of 1,25(OH) 2 D 3 (6). PTH stimulates 1␣(OH)ase transcription, resulting in increased 1,25(OH) 2 D 3 synthesis (7-9). However, under normocalcemic conditions, PTH fails to stimulate 1␣(OH)ase expression (10). Previous studies showed that calcitonin can enhance renal conversion of 25(OH)D 3 to 1,25(OH) 2 D 3 and that calcitonin, not PTH, is the major regulator of 1␣(OH)ase in the normocalcemic state (10 -13). In early development and during pregnancy and lactation calcitonin levels are increased under normocalcemic conditions and correlated to an increase in serum 1,25(OH) 2 D 3 levels (14 -17). The stimulation of 1,25(OH) 2 D 3 under normocalcemic conditions by calcitonin m...

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Section: Discussionmentioning

confidence: 97%

Calcitonin, a Regulator of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene

Zhong

Armbrecht

Christakos

2009

Journal of Biological Chemistry

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“…This study used female mice at 8 to 10 weeks of age. For EAE induction mice were injected subcutaneously with 100 g of myelin oligodendrocyte glycoprotein (MOG) amino acids 35-55 (MOG peptide MEVGW-YRSPFSRVVHLYRNGK) 39 and 1 mg of heat-killed Mycobacterium tuberculosis H37RA emulsified in complete Freund's adjuvant (Difco, Lawrence, KS). 200 ng of pertussis toxin (List Biological Laboratories) was injected intraperitoneally on days 0 and 2 after immunization.…”

Section: Animals and Eae Inductionmentioning

confidence: 99%

“…39 Disease was also assessed using histological examination of CNS tissue as previously described. 40 Briefly, animals were perfused with 20 ml of cold phosphate-buffered saline, and CNS tissue was excised and fixed in formal saline.…”

Section: Animals and Eae Inductionmentioning

confidence: 99%

“…39 Briefly, tissue was cut into small pieces and digested for 40 minutes at 37°C in media (GIBCO, Auckland, New Zealand) supplemented with 1.4 mg/ml collagenase H (Roche, Mannheim, Germany) and 100 g/ml DNase I (Roche). Resulting tissue homogenates were forced through a 70-m cell strainer and leukocytes were enriched using a discontinuous 40%/80% Percoll density gradient centrifugation.…”

Section: Cell Isolation and Purificationmentioning

confidence: 99%

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Synthetic Retinoid AM80 Inhibits Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis

Klemann

Raveney

Klemann

et al. 2009

The American Journal of Pathology

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Recent evidence suggests that interleukin-17-producing CD4؉ T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3 ؉ regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of ROR␥t and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and ROR␥t. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells. (Am J Pathol

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“…This suggests an anti-inflammatory function for Nr4a2; however, many pro-inflammatory roles for this receptor have also been reported (23)(24)(25).…”

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confidence: 97%

Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis

Mahajan

Saini

Chandra

et al. 2015

Journal of Biological Chemistry

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Background: An understanding of the role of Nr4a2 in inflammation is needed. Results: Nr4a2 is a transcription factor that induces expression of M2 characteristic genes, and adoptive transfer of macrophages overexpressing Nr4a2 gives protection against septic mortality. Conclusion: Our data impart a new role for Nr4a2 in skewing macrophage plasticity to M2 type. Significance: Therapeutic intervention of Nr4a2 may provide a cure for inflammatory diseases.

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Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines

Cited by 81 publications

References 41 publications

Calcitonin, a Regulator of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene

Calcitonin, a Regulator of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene

Synthetic Retinoid AM80 Inhibits Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis

Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis

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