Upregulation of the stress‐associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues

Plant, Sheila R.; Wang, Ying; Vasseur, Sophie; Thrash, J. Cameron; McMahon, Eileen; Bergstralh, Daniel T.; Arnett, Heather A.; Miller, Stephen D.; Carson, Monica J.; Iovanna, Juan; Ting, Jenny P.‐Y.

doi:10.1002/glia.20297

Cited by 21 publications

(16 citation statements)

References 23 publications

(36 reference statements)

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“…3A, TCR-b and Th1-cytokine (IFN-g, Lymphotoxin-a) transcript levels were increased in CNS from Ovx mice that developed significantly worse EAE than sham-operated controls. Likewise, we found that mRNA of various chemokines (TCA-3, MCP-1, C10, RANTES, MIG, MDC) known to be early upregulated in the CNS from mice developing EAE [18] and expression of the stress-associated gene P8, which is linked with active demyelination [19], were higher in Ovx mice relative to shamoperated control (Supporting Information Fig. 5A and B).…”

Section: Resultsmentioning

confidence: 69%

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

et al. 2010

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Sex hormones influence immune responses and the development of autoimmune diseases including MS and its animal model, EAE. Although it has been previously reported that ovariectomy could worsen EAE, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been addressed. In this report, we now show that endogenous estrogens limit EAE development and CNS inflammation in adult female mice through estrogen receptor a expression in the host non-hematopoietic tissues. We provide evidence that the enhancing effect of gonadectomy on EAE development was due to quantitative rather than qualitative changes in effector Th1 or Th17 cell recruitment into the CNS. Consistent with this observation, adoptive transfer of myelin oligodendrocyte glycoprotein-specific encephalitogenic CD41 T lymphocytes induced more severe EAE in ovariectomized mice as compared to normal female mice. Finally, we show that gonadectomy accelerated the early recruitment of inflammatory cells into the CNS upon adoptive transfer of encephalitogenic CD4 1 T cells. Altogether, these data show that endogenous estrogens, through estrogen receptor a, exert a protective effect on EAE by limiting the recruitment of blood-derived inflammatory cells into the CNS.Key words: EAE/MS . Estrogen . Estrogen receptor . Inflammation . Th1/Th17 cells Supporting Information available onlineIntroduction MS and its prototypic animal model, EAE, are autoimmune demyelinating diseases of the CNS. In MS and EAE, the inflammatory process is mediated by T lymphocytes reactive to CNS and brain autoantigens. It is well documented that sex hormones could influence immune responses and the development of autoimmune diseases including MS and EAE [1]. Indeed, protective effects of exogenous estrogens have been extensively reported in animal models of EAE [2][3][4]. The actions of estrogens are mediated primarily through nuclear estrogen receptor (ER) a and ERb [5]. Analysis of the effect of exogenous 17b-estradiol 3489(E2) on EAE induction in ER-mutant mice clearly showed that this protective effect of E2 was mediated through ERa but not ERb [6][7][8]. Altogether, these studies support a protective role of estrogens on EAE that could explain the protective effect of pregnancy on MS [9]. Indeed, a clinical trial in women with MS has documented a beneficial effect of exogenous estriol administration [10]. Thus, although it has been shown that exogenous estrogens down modulate EAE through ERa, it is still unclear whether physiological levels of endogenous estrogens can significantly influence CNS autoimmunity [11,12]. In female mice, sex steroid hormones, such as estrogens, are mainly produced by the ovaries, and previous studies have reported that ovariectomy could worsen EAE [2,13,14]. However, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been previously examined. For instance, it is still unknown whether these effects were due to ovarian-derived estrogens or other gonadal hormones, and whether classical ER...

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Section: Resultsmentioning

confidence: 69%

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

et al. 2010

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“…Induction of p8 mRNA is rapid, strong, and transient in response to divergent stresses such as systemic LPS or CCl 4 (13,14), demyelination-inducing agents (15), serum withdrawal (2), and chemical inducers of cell cycle arrest (16). p8 is also induced in response to TGF␤ (7), TNF␣ (10,17), glucose (18), cannabinoids (12), 1,25-dihydroxyvitamin D 3 (19), angiotensin, and ET (20) ( Table 1).…”

Section: P8 Structure and Expressionmentioning

confidence: 99%

Stress-inducible Protein p8 Is Involved in Several Physiological and Pathological Processes

Goruppi

Iovanna

2010

Journal of Biological Chemistry

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p8 (NUPR1 (nuclear protein-1), Com1 (candidate of metastasis-1)) is a protein related to the high mobility group of transcriptional regulators. It is a key player in the cellular stress response and is involved in metastasis. p8 was first identified as a gene induced in pancreatitis but has been since found overexpressed in several cancers and pathological conditions. Despite its small size and apparently simple structure, p8 functions in several biochemical and genetic pathways, and its expression is crucial for in vivo metastasis in mice, for cytokine induction of metalloproteases, and for stress-induced cardiomyocyte hypertrophy. Understanding p8 functions will provide new opportunities for developing more effective therapeutic approaches to cancer and cardiovascular diseases. p8 Structure and Expressionp8/com1/NUPR1 (p8 herein) was first described as a gene strongly induced in pancreatic acinar cells during the acute phase of pancreatitis (1). p8 is a conserved gene with homologs in mammals and Drosophila (2) and in Xenopus (3) (Fig. 1). Human p8 encodes an 82-amino acid polypeptide with a theoretical molecular mass of 8872.7 Da and a pI of 9.98. The p8 protein contains a canonical bipartite nuclear localization signal (4) and an N-terminal PEST (Pro/Glu/Ser/Thr-rich) region, suggesting a regulation of p8 protein levels by the ubiquitin/ proteasome system. At its C terminus, p8 contains a basic helixloop-helix motif (5). Alternative splicing produces an isoform with 18 additional amino acids, named isoform a, and both the tissue expression and the possible functional differences for this additional isoform are unknown. So far, all of the biochemical and molecular biological studies of p8 have been performed with the shorter isoform, isoform b.Aside from a modest similarity (35%) to HMG 3 proteins, especially HMG-I/Y proteins, numerous data base searches indicate that p8 shares no strong homology with other proteins. Consistent with its structural similarity to HMG proteins, p8 exhibits some biochemical properties similar to HMG proteins. Thus, the molecular mass, isoelectric point, hydrophilicity plot, heat stability, and charge distribution are very similar to those of HMG proteins.NMR and CD analyses of the recombinant protein indicate that p8 does not assume a stable secondary structure. p8 binds DNA weakly without apparent preference for DNA sequence. Human p8 is a substrate for protein kinase A in vitro; phosphorylated p8 has a higher content of secondary structure, and its binding to DNA is highly increased (6). In addition, p8 can undergo acetylation, ubiquitination, and sumoylation. These observations, plus the known nuclear localization of p8, suggested a role for p8 in transcriptional regulation (5,(7)(8)(9)(10)(11)(12).

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“…The stress-associated gene P8 is a newly identified marker that is associated with active demyelination (35). We used realtime PCR to quantitate P8 gene expression in the spinal cords of Astro CD24TG mice and NTG mice on day 20 (peak of disease) and day 40 (EAE recovery) after immunization.…”

Section: Neurogenesis and Remyelination Levels Are Similar In Cd24 Trmentioning

confidence: 99%

CD24 on the Resident Cells of the Central Nervous System Enhances Experimental Autoimmune Encephalomyelitis

Liu

Carl

Joshi

et al. 2007

The Journal of Immunology

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CD24 is a cell surface glycoprotein that is expressed on both immune cells and cells of the CNS. We have previously shown that CD24 is required for the induction of experimental autoimmune encephalomyelitis (EAE), an experimental model for the human disease multiple sclerosis (MS). The development of EAE requires CD24 expression on both T cells and non-T host cells in the CNS. To understand the role of CD24 on the resident cells in the CNS during EAE development, we created CD24 bone marrow chimeras and transgenic mice in which CD24 expression was under the control of a glial fibrillary acidic protein promotor (AstroCD24TG mice). We showed that mice lacking CD24 expression on the CNS resident cells developed a mild form of EAE; in contrast, mice with overexpression of CD24 in the CNS developed severe EAE. Compared with nontransgenic mice, the CNS of AstroCD24TG mice had higher expression of cytokine genes such as IL-17 and demyelination-associated marker P8; the CNS of AstroCD24TG mice accumulated higher numbers of Th17 and total CD4+ T cells, whereas CD4+ T cells underwent more proliferation during EAE development. Expression of CD24 in CD24-deficient astrocytes also enhanced their costimulatory activity to myelin oligodendrocyte glycoprotein-specific, TCR-transgenic 2D2 T cells. Thus, CD24 on the resident cells in the CNS enhances EAE development via costimulation of encephalitogenic T cells. Because CD24 is increased drastically on resident cells in the CNS during EAE, our data have important implications for CD24-targeted therapy of MS.

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Upregulation of the stress‐associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues

Cited by 21 publications

References 23 publications

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

Stress-inducible Protein p8 Is Involved in Several Physiological and Pathological Processes

CD24 on the Resident Cells of the Central Nervous System Enhances Experimental Autoimmune Encephalomyelitis

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Upregulation of the stress‐associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues

Cited by 21 publications

References 23 publications

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4+ T‐cell homing into the CNS

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4+ T‐cell homing into the CNS

Stress-inducible Protein p8 Is Involved in Several Physiological and Pathological Processes

CD24 on the Resident Cells of the Central Nervous System Enhances Experimental Autoimmune Encephalomyelitis

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Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS