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An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization
Laval University, Quebec City, Quebec, CanadaThe FASEB Journal (Impact Factor: 5.04). 11/2005; 19(12):1668-70. DOI: 10.1096/fj.04-2030fje
Inflammation in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), is manifested by changes in matrix metalloproteinase (MMP) expression and in the ratio of T helper (Th) 1 and 2 effector cytokines. Here, we provide a comprehensive documentation of MMPs in EAE and report that of all the MMPs that could be measured at peak disease in spinal cord tissue, MMP-12 was the most highly up-regulated. In contrast to previously published findings of MMPs in EAE, this increase in MMP-12 expression was associated with protection, as MMP-12 null mice had significantly worse maximum severity and EAE disease burden compared with wild-type (WT) controls. When spleen and lymph node cells were removed from EAE-afflicted WT and MMP-12 null mice at the same disease score before divergence of disease and restimulated in vitro, the MMP-12 null cells had significantly higher Th1 to Th2 cytokine ratio. Measurements of the transcriptional regulators of T cell polarization revealed that MMP-12 null cells had increased T-bet and reduced GATA-3 expression, a condition that favors a Th1 bias. These results emphasize that specific MMPs can have beneficial roles in inflammation, and they implicate MMPs in T effector polarization for the first time.
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[Show abstract] [Hide abstract] ABSTRACT: Background: Tumor cell migration and diffuse infiltration into brain parenchyma are known causes of recurrence after treatment in Glioblastoma (GBM), mediated in part by the interaction of glioma cells with the extracellular matrix, followed by degradation of matrix by tumor cell derived proteases, particularly the matrix metalloproteinases (MMP). Sevoflurane and thiopental are anesthetics commonly used in cancer surgery. However, their effect on the progression of glioma cells remains unclear. The aim of this study was to explore the role of these anesthetics on the migration and activity of MMP-2 in glioma cells. Methodology: Cultured U87MG cells were pretreated with sevoflurane or thiopental and in vitro wound healing scratch assay was carried out to analyze their effect on migration of these cells. Gelatin zymography was carried out to examine the effect of these anesthetics on tumor cell MMP-2 activity using the conditioned media 24h after pretreatment. Cell viability was analyzed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Results: U87MG cells exposed to 2.5% sevoflurane or different concentrations of thiopental significantly decreased migration and activity of MMP-2 compared to control. No effect was seen on the viability of these cells after pretreatment with sevoflurane or thiopental. Conclusion/significance: These results suggest that both sevoflurane and thiopental have inhibitory effect on the migration and MMP-2 activity in glioma cells. Thus, it is important that the choice of anesthetics to be used during glioma surgery takes into account their inhibitory properties against the tumor cells.
- "In contrast to glioma and various other neurological disorders of the central nervous system (CNS), in which MMP-2 is significantly upregulated (Yong et al., 2005), the normal adult CNS contains low levels of most MMP members (Weaver et al., 2005). In the normal adult brain, cell migration is mainly restricted to the migration of neuronal precursors in the dentate gyrus of the hippocampus (Kaplan and Bell, 1984; Seki, 2002) and the subventricular zone (Lois and Alvarez-Buylla, 1994). "
[Show abstract] [Hide abstract] ABSTRACT: Previous work has demonstrated that the hormone prolactin promotes oligodendrocyte precursor proliferation and remyelination following lysolecithin-induced demyelination of the mouse spinal cord. Prolactin, however, can elicit pro-inflammatory responses, and its use in the prototypical demyelinating and inflammatory condition, multiple sclerosis (MS), should thus be approached cautiously. Here, we sought to determine whether recombinant prolactin could alter the course of experimental autoimmune encephalomyelitis (EAE), an inflammatory animal model of MS. Consistent with previous literature, we found that prolactin activated leukocytes in vitro. Daily treatment with prolactin from around the time of onset of clinical signs, for 9 (days 9 to 17) or 25 (days 9 to 33) days did not increase clinical or histological signs of EAE over that of vehicle-treated mice. Instead, the combination of prolactin and a suboptimal dose of recombinant murine interferon-beta resulted in (days 9 to 17 group) or trended towards (days 9 to 33 group), a greater amelioration of clinical signs of EAE, compared to either treatment alone or to vehicle controls. Histological analyses corroborated the clinical EAE data. These results suggest that prolactin may be beneficial when administered in combination with interferon-beta in MS.
- "The dose of 20 μg prolactin/mouse/day was chosen as this was the pro-remyelinating dose in the lysolecithin demyelinating model in mice . We found that EAE-afflicted mice treated with vehicle attained peak clinical severity of between 4 and 6 on the 15-point scale , representing tail and hind-limb disability (Figure 1A); this modest disease severity provided room to reveal a pro-disease exacerbating effect, as EAEafflicted mice often have involvement of forelimb disability in other experiments (data not shown). Prolactin treatment did not exacerbate EAE clinical severity over that of vehicle-treated EAE mice (Figure 1A), and a suboptimal dose of recombinant murine IFN-β also did not affect EAE clinical severity. "
[Show abstract] [Hide abstract] ABSTRACT: Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1-but not pertussis toxin, which affects Gi protein-dependent responses-abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis.
- "B). EAE reactions were scored and recorded accordingly to a 0–15 scale, as described (Weaver et al., 2005). In the scoring based on a 0–15 scale, the final score is the sum of the state of the tail and all of the four limbs. "