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Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement.

Trysberg E, Blennow K, Zachrisson O, Tarkowski A - Arthritis Res. Ther. (2004)

Bottom Line: Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay.Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012).In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Rheumatology and Inflammation Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden. Estelle@immuno.gu.se

ABSTRACT
Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.

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Scattergram showing relationship between IL-8 and matrix metalloproteinase (MMP)-9 in cerebrospinal fluid of all patients with systemic lupus erythematosus (r = 0.47; P < 0.0001).
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Figure 3: Scattergram showing relationship between IL-8 and matrix metalloproteinase (MMP)-9 in cerebrospinal fluid of all patients with systemic lupus erythematosus (r = 0.47; P < 0.0001).

Mentions: CSF levels of IL-6 (47 ± 25 pg/ml versus 15 ± 3 pg/ml; P < 0.008) and IL-8 (91 ± 23 pg/ml versus 45 ± 6 pg/ml; P < 0.05) were both significantly increased in CSF from patients with CNS lupus as compared with cerebrally healthy SLE patients, supporting our previous findings [15,19]. Importantly, intrathecal levels of IL-6 and IL-8 significantly correlated with those of MMP-9 (r = 0.30 [P < 0.002] and r = 0.47 [P < 0.0001], respectively; Table 3 and Fig. 3). A neuronal degeneration marker (protein tau) and an astrocytic degeneration marker (glial fibrillary acidic protein) were both significantly increased in CSF from NPSLE patients as compared with CSF from SLE patients who were clinically free from CNS involvement (311 ± 78 pg/ml versus 178 ± 16 pg/ml [P < 0.05] and 1288 ± 708 pg/ml versus 396 ± 30 pg/ml [P < 0.009]), in concordance with previous findings [28,32]. Importantly, a significant correlation was noted between intrathecal MMP-9 and levels of tau and glial fibrillary acidic protein (P < 0.05 in both cases; Table 3).


Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement.

Trysberg E, Blennow K, Zachrisson O, Tarkowski A - Arthritis Res. Ther. (2004)

Scattergram showing relationship between IL-8 and matrix metalloproteinase (MMP)-9 in cerebrospinal fluid of all patients with systemic lupus erythematosus (r = 0.47; P < 0.0001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064867&req=5

Figure 3: Scattergram showing relationship between IL-8 and matrix metalloproteinase (MMP)-9 in cerebrospinal fluid of all patients with systemic lupus erythematosus (r = 0.47; P < 0.0001).
Mentions: CSF levels of IL-6 (47 ± 25 pg/ml versus 15 ± 3 pg/ml; P < 0.008) and IL-8 (91 ± 23 pg/ml versus 45 ± 6 pg/ml; P < 0.05) were both significantly increased in CSF from patients with CNS lupus as compared with cerebrally healthy SLE patients, supporting our previous findings [15,19]. Importantly, intrathecal levels of IL-6 and IL-8 significantly correlated with those of MMP-9 (r = 0.30 [P < 0.002] and r = 0.47 [P < 0.0001], respectively; Table 3 and Fig. 3). A neuronal degeneration marker (protein tau) and an astrocytic degeneration marker (glial fibrillary acidic protein) were both significantly increased in CSF from NPSLE patients as compared with CSF from SLE patients who were clinically free from CNS involvement (311 ± 78 pg/ml versus 178 ± 16 pg/ml [P < 0.05] and 1288 ± 708 pg/ml versus 396 ± 30 pg/ml [P < 0.009]), in concordance with previous findings [28,32]. Importantly, a significant correlation was noted between intrathecal MMP-9 and levels of tau and glial fibrillary acidic protein (P < 0.05 in both cases; Table 3).

Bottom Line: Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay.Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012).In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Rheumatology and Inflammation Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden. Estelle@immuno.gu.se

ABSTRACT
Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.

Show MeSH
Related in: MedlinePlus