Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview

Chandler, Stephen F.; Miller, Karen; Clements, John M.; Lury, Jon; Corkill, Dominic J.; Anthony, Daniel C.; Adams, Sally E.; Gearing, A. J. H.

doi:10.1016/s0165-5728(96)00179-8

Cited by 251 publications

(161 citation statements)

References 75 publications

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“…Interestingly, the expression of various MMPs is increased in MS [10,31] and EAE [8]. Inhibitors of MMP also block the development of EAE [4,17,22]. The effects of PPAR-γ agonists on MMP expression in the CNS have not been thoroughly investigated.…”

Section: Ppar-γ: Effects On Peripheral Leukocytesmentioning

confidence: 99%

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Drew

Storer

et al. 2005

Brain Research Reviews

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses.Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-α that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS.Previously, we and others demonstrated that PPAR-γ agonists including 15d-PGJ 2 are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-γ modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ 2 is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ 2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ 2 and 9-cis RA inhibit cell activation through the formation of PPAR-γ/ RXR heterodimers. Interestingly, PGA 2 , which like 15d-PGJ 2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ 2 does not bind PPAR-γ, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ 2 inhibits microglial cell activation by PPAR-γ-dependent as well as PPAR-γ-independent mechanisms. The studies further suggest that the PPAR-γ agonist 15d-PGJ 2 in combination with retinoids may be effective in the treatment of MS.

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Section: Ppar-γ: Effects On Peripheral Leukocytesmentioning

confidence: 99%

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Drew

Storer

et al. 2005

Brain Research Reviews

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“…Interestingly the ligands are expressed as transmembrane proteins but soluble forms have been identified for all of them (Schneider and Tschopp, 2000). The soluble forms are generated through the activity of metalloproteinases (Kayagaki et al, 1995;Chandler et al, 1997;Black et al, 1997;Mariani and Krammer, 1998;Itai et al, 2001). It has not been determined if there are specific metalloproteases for each ligand.…”

Section: Death Receptor Proteinsmentioning

confidence: 99%

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Holmes¹,

Soprano²,

Soprano³

2004

Journal Cellular Physiology

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Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N-[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR.

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“…Although the cause of MS remains unknown, acquired immunity, including T-and B-cell responses targeting myelin proteins, determines the early stages of disease, whereas innate immune mechanisms with macrophage/microglia activation are pivotal in disease initiation and progression together with the selective expression and release of inflammatory mediators by activated immune cells, such as cytokines (Navikas and Link, 1996), chemokines (Bar-Or et al, 1999;Sorensen et al, 1999), and MMPs (Chandler et al, 1997;Yong et al, 1998). Several immunomodulatory agents inhibit the development of disease in an animal model of MS, experimental autoimmune encephalomyelitis (EAE) (Miller and Shevach, 1998;Neuhaus et al, 2003), and in some cases have been shown to influence the course of human disease (Neuhaus et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui¹,

Schnermann²,

Noorbakhsh³

et al. 2004

J. Neurosci.

298

265

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The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR Ϫ/Ϫ ) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR ϩ/ϩ ) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR Ϫ/Ϫ animals. In addition, spinal cords from A1AR Ϫ/Ϫ mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR ϩ/ϩ animals. Macrophages from A1AR Ϫ/Ϫ animals exhibited increased expression of the proinflammatory genes, interleukin-1␤, and matrix metalloproteinase-12 on immune activation when matched with A1AR ϩ/ϩ control cells. A1AR Ϫ/Ϫ macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR ϩ/ϩ mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis (MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases.

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Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview

Cited by 251 publications

References 75 publications

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

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