Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways
© Green et al; licensee BioMed Central Ltd. 2011
Received: 15 November 2010
Accepted: 11 May 2011
Published: 11 May 2011
Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.
Central nervous system (CNS) tuberculosis (TB) is heavily over represented in mortality figures causing over 30% of adult TB deaths [1, 2]. This is because the marked CNS inflammatory response to the pathogen is poorly tolerated. CNS TB is an encephalomyelitis with invasion of parenchymal brain tissue. The mechanisms resulting in CNS invasion and tissue destruction are poorly defined but are known to involve pathogen-driven host-derived factors [3, 4].
Matrix metalloproteinases (MMPs) are a family of 23 zinc containing endopeptidases that degrade extracellular matrix, facilitate leukocyte recruitment, process cytokines and chemokines, as well as cleave cell surface molecules leading to intracellular signaling events . MMP activity is controlled at the transcriptional level and by tissue inhibitors of metalloproteinase (TIMP-1 to -4), as well as by compartmentalization and secretion of pro-forms (zymogens). MMPs have a pivotal role in diseases with marked inflammatory phenotypes such as rheumatoid arthritis , sarcoidosis  and atherosclerosis  as well as CNS disorders like multiple sclerosis  and HIV encephalitis . There is growing evidence on their role in the pathogenesis of TB [11–14]. An emerging concept is that important balances exist, not only between MMPs and TIMPs, but also between different MMPs with similar substrate affinity meaning that changes in MMP concentrations may be an important regulatory mechanism [15, 16].
Control of gene regulation by binding of transcription factors such as NFκB is key in control of specific MMPs. Most MMPs (e.g. MMP-1, -3, -7, -8, -9, -11, -12, -13, -19 and -26) have a TATA box at -30 bp from the transcriptional start site. However, MMP-2, -14 and -28 lack the TATA box often resulting in high levels of constitutive expression [17–19]. Steroids, which are transcriptional regulators of MMP gene expression, have a clinically proven beneficial effect in CNS TB which we have shown may be due in part to their influence on MMP secretion [20, 21]. Additionally, upstream signaling molecules including the p38 mitogen activated protein kinases (MAPK) regulate both MMP gene transcription and post-transcriptional gene stability [22, 23]. Proteolytic cleavage of these kinases and signal transducers by caspases is usually an inactivation step during apoptosis. However, some kinases such as MEK kinase-1 are activated by caspase-3 mediated cleavage . There are few published data on the control of MMP secretion by caspases although caspase 8 has been reported to phosphorylate STAT1 and thus regulate IFN-γ suppression of MMP-9 secretion . Additionally caspases may induce apoptosis via an MMP-3 dependent process .
MMP-2 degrades basement membrane, type IV collagen, gelatin, aggrecan and laminin . Nonsense mutations in the human MMP-2 gene result in phenotypic changes defined clinically as the Torg, Winchester and Nodulosis-Arthropathy-Osteolysis syndromes . MMP-2 is constitutively expressed at high levels by many cells and is regulated by pro-peptide activation [12, 18]. In the CNS, MMP-2 drives neuronal apoptosis and breakdown of CNS specific substrates such as dystroglycan, a transmembrane receptor involved in anchoring of astrocyte endfeet to the basement membrane via laminin binding . However, substrate overlap exists as dystroglycan is also cleaved by MMP-9 with Mmp2Mmp9 null mice protected from neuroinflammation in an EAE model . Cellular influx into areas of inflammation is regulated by MMP-2 activity. For example, HIV infected microglia/macrophages secreted proMMP-2 which is activated by neuronal MMP-14 and cleaves astrocyte-derived CXCL12 (SDF-1) that is itself neurotoxic and HIV-infected leucocytes up-regulate MMP-2 (and -9) secretion in order to cross the blood brain barrier (BBB) [10, 30]. MMP-2 is thus an effector of tissue destruction in the CNS and mechanisms that lead to its suppression may be neuroprotective.
There are few published data on MMP-2 in TB but we and others have shown that cerebrospinal fluid concentrations are raised in TBM with no concomitant rise in TIMP-1 or -2 [21, 31, 32]. In addition, MMP-2 has been detected by immunohistochemistry in meninges of CNS TB patients . In CNS TB excess MMP-2 is likely to be secreted by microglial cells, the resident innate cells of the CNS, as TB infected monocytes/macrophages do not secrete MMP-2 and astrocytes do not alter MMP-2 secretion in response to TB infection [11, 12]. Therefore we investigated mechanisms regulating MMP-2 gene expression and secretion in a simplified cellular model of CNS TB.
Chemicals for microglial inhibition, including the caspase 8 inhibitor (z-IETD-fmk) were from Sigma-Aldrich (Gillingham, UK), tissue culture materials from Invitrogen (Paisley, UK) and tissue culture plastic from TPP (Trasadingen, Switzerland) unless otherwise stated. Anti-TNF-α neutralizing antibodies, recombinant TNF-α, IL-1Ra, recombinant IL-1β were from Peprotech (Rocky Hill, NJ, US). SB203580, PD98059, SP600125 and SC-514 were purchased from Calbiochem (Merck, Nottingham, UK), helenalin from Biomol (Exeter, UK).
M.tb culture and colony counting
The virulent M.tb strain H37Rv Pasteur was cultured from frozen stocks in Middlebrook 7H9 broth with 10% OADC enrichment medium (BD Biosciences, Oxford, UK), 0.2% glycerol, and 0.02% Tween 80 in a shaking incubator. An optical densitometer (Biowave Cell Density Meter, WPA, Cambridge, UK) was used to assess growth of M.tb. Experiments were performed with cultures having an OD of 0.6 after 30 seconds sonication. The endotoxin level was <0.03 ng/ml LPS as measured by amoebocyte lysate assay (Associates of Cape Cod, East Falmouth, MA, US). Multiplicity of infection (MOI) used in each experiment was checked by colony counts on Middlebrook 7H11 agar containing ADC enrichment medium (BD Biosciences) and amphotericin 2.5 μg/ml. Tb medium was generated by centrifuging M.tb at OD 0.6 at 11,700 RCF (13,000 RPM) for 5 minutes and then sterile filtering the supernatant through an Anopore 0.2 mM membrane (Anopore, Brentford, UK).
Monocyte isolation and M.tb infection
PBMCs were isolated from single healthy blood donor residual buffy coats (UK Blood Transfusion Service) using Ficoll-Paque (GE Healthcare, Little Chalfont, UK) density gradient centrifugation and a standard adherence protocol . Monocytes were stimulated by M.tb at an MOI of 1 or 7H9 medium alone. At 24 hours, cell culture medium was collected and filtered via a 0.2-μm pore size sterile filter (Anopore) to remove infectious particles. This conditioned medium from M.tb infected monocytes was termed CoMTb and conditioned medium from uninfected, control monocytes termed CoMCont. Similarly CoACont and CoATb were produced from infecting primary human astrocytes with M.tb but at MOI of 10 in serum free Modified Eagle's Medium (MEM) after preliminary experiments showed no effect of an MOI of 1 (data not shown) and no excess cell death with an MOI of 10.
Human CHME3 microglial cells (a gift of Professor Marc Tardieu, Paris, France and donated by Dr Nicola Woodroofe, Sheffield Hallam University, UK) were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% FCS (Biosera, Ringmer, UK) and 3 mM glutamine in a humidified incubator with 5% CO2 at 37°C. For experiments cells were seeded the day previously at 35-50,000 cells/cm2 (to ensure that MOI was little affected by replication as previous data confirmed no change in infectivity ) and performed in macrophage serum free medium (MSFM). Cell culture medium was not replaced and harvested at specified time points, centrifuged for 5 minutes at 12,000 g to remove cellular debris and samples frozen at -20°C for later analysis. In direct infection experiments, M.tb was removed by filtration of all samples through a 0.2-μm pore size Durapore sterile filter (Millipore, Watford, UK) to remove infectious particles but retain MMP activity .
Zymography is substrate based SDS-PAGE electrophoresis which provides data on all the potentially active MMP present in the sample analyzed . Enzyme activity is seen as white bands on Comassie blue stained gels . A 0.2 ng MMP-9 standard (Oncogene, CA, US) was run on each gel to compensate for gel to gel variability and gels run as previously described . Gels were analyzed densitometrically by digital image capture (UVP Transilluminator, Cambridge, UK) and by Scion Image Analysis software (NIH Image version 1.61, Bethesda, MD, US).
Analysis of MMP-2 by Luminex multianalyte technology
Total immunoreactive MMP-2 concentrations (pro-, active and degraded) were analyzed for MMP-2 secretion using Fluorokine multianalyte profiling kits (R&D Systems, Abingdon, UK) and the Luminex platform Bio-Plex 200 system (Bio-Rad, Watford, UK). Bio-Plex manager software (version 5.0) was used to construct standard curves and calculate unknowns. The minimum level of detection for MMP-2 was 80 pg/ml.
Gene expression analysis by real time quantitative PCR
Microglia were lysed with TRI Reagent and total RNA was extracted using a standard chloroform-phenol-isopropanol protocol using phase-lock-gel tubes (Eppendorf, Cambridge, UK) . RNA was further purified by a DNAse step using a commercial kit (Ambio, Austin TX, US). Reverse transcription of 1 μg RNA was followed by quantitative polymerase chain reactions (qPCRs) performed in a 25 μL reaction with a Stratagene Mx3000P machine (Stratagene, La Jolla, CA, US) using 5 ng cDNA, Brilliant II qPCR mastermix (Stratagene) and MMP primers and probes as described previously . The cycle threshold (CT) at which amplification entered the exponential phase was determined and this number was used to indicate the amount of target RNA in each sample. The MMP CT calculated was also normalized to ribosomal 18s CT run concurrently.
Standard western blotting was performed. For p38 MAP kinase analysis cells were lysed using 200 μl of SDS sample buffer (62.5 mM Tris pH 6.8, 2% SDS, 10% glycerol, 50 mM DTT and 0.01% bromophenol blue) and immediately frozen at -80°C. 40 μl aliquots were run as described . Overnight incubation in 1:1000 rabbit primary antibodies to both phosphorylated and unphosphorylated variants of p38 was followed by washing and incubation with 1:2000 dilution of anti-rabbit HRP-linked secondary antibody (both Cell Signaling Technology, MA, US). Bands were visualized by chemiluminescence with the ECL plus system (GE Healthcare) according to manufacturer's instructions. Anti-caspase 8 p18 subunit rabbit polyclonal primary antibody (Santa Cruz, CA, US) was used at 1:1000 dilution with the same secondary outlined above.
Ethical consent for the study of anonymized paraffin embedded sections from the histopathology archive was obtained from the Hammersmith Hospitals Research Ethics Committee in accordance with The Human Tissue Act 2004. Formalin-fixed and paraffin embedded brain biopsies from five immunocompetent patients with biopsy-proven CNS M.tb infection, two negative controls (the superior frontal and the superior temporal gyri of normal post-mortem brains with no pathological changes) and two positive controls (patients who had undergone temporal lobectomy epilepsy surgery) were immunostained for the microglial marker Iba1 (rabbit polyclonal antibody, Wako, Osaka, Japan, dilution 1:400) and phospho-p38 (mouse monoclonal, Sigma-Aldrich, dilution 1:200) as well as standard H&E staining. Five μm sections were deparaffinised in xylene and rehydrated in alcohol. Endogenous peroxidase activity was blocked with 0.3% hydrogen peroxide in PBS for 30 minutes and antigen retrieval of sections was performed by steaming the sections in citrate buffer (0.01 M citrate pH 6.5) for 30 minutes. Sections were then incubated with 10% normal goat serum (Vector Laboratories, Burlinghame, CA, US) for 20 minutes at room temperature. The primary antibody was applied overnight at 4°C. The following day staining was visualized using biotinylated secondary antibodies followed by avidin-biotin peroxidase complex (Vectastain Elite ABC kit, Vector Laboratories, Burlingham, CA, US). The reaction product was revealed with 2 μg/mL 3, 3'-Diaminobenzidine (DAB) and 0.0075% hydrogen peroxide in PBS. Slides were counterstained with hematoxylin and coverslipped. Methodological negative controls included omission of the primary antibody.
Preparation of nuclear & cytoplasmic extracts
30 minute timepoint nuclear and cytoplasmic extracts were prepared using a commercial kit (Active Motif, Rixensart, Belgium) according to the manufacturer's instructions. To ensure equal total protein loading of samples between wells in subsequent Western and ELISA assays of cell lysates a Bradford assay was used to calculate total protein concentration in samples.
Detection of nuclear NFκB DNA binding
To investigate activation of NFκB subunits a specific transcription factor assay (TransAM, Active Motif) with primary antibodies to p50 and p65 was used. Competition experiments demonstrated specificity of binding by adding 20 pM/well of either wildtype or mutated NFκB oligonucleotide before assaying with the p65 antibody and demonstrating loss of binding with wildtype but not mutated construct. Values are expressed as fold change normalized to control conditions.
Microglial MMP-2 secretion is suppressed more by CoMTb than by direct infection
TNF-α but not IL-1β in CoMTb suppresses microglial MMP-2 secretion
p38 and ERK MAPK divergently regulate CoMTb-mediated MMP-2 secretion
NFκB signalling suppresses MMP-2 gene expression
Caspase 8 inhibition restores CoMTb-induced MMP-2 secretion to control concentrations
Next, we investigated the influence of the caspase 8 pathway on p38 MAPK. Caspase 8 inhibition led to a paradoxical increase in p38 phosphorylation at 30 minutes (Figure 6C). There were no differences in cell numbers during these experiments. Finally, we investigated whether caspase 8 might act via the NFκB pathway. Both p50 and p65 NFκB subunits were up-regulated in nuclear extracts from CoMTb-stimulated microglial cells by 30 minutes. However, caspase 8 acts independently of p65/p50 NF-kB nuclear translocation (Figure 6D).
In this study, we demonstrated that a TNF-dependent cytokine network involving M.tb-infected monocytes, but not direct infection by M.tb, down-regulates MMP-2 secretion from microglial cells via p38 MAP kinase, NFκB and caspase 8 pathways. Since M.tb infection and TNF-α usually drive gene expression and secretion of other MMPs, such as MMP-1, -3 and -9, leading to pro-inflammatory damage this was an unexpected, paradoxical finding [33, 37, 42]. Specifically this was the only down-regulated molecule when studying all MMPs in this model system in our previously published work and in particular contrast to the other gelatinase MMP-9 . p38 staining has never previously been demonstrated in vivo in human microglia. Caspase 8 has not been implicated in the regulation of MMP secretion in TB.
In our simplified cellular model of CNS TB, MMP-2 secretion was suppressed up to 96 hours by CoMTb more profoundly than by M.tb alone. The effect of monocyte-microglial networks was specific since neither astrocyte nor microglial-derived conditioned medium affected MMP-2 secretion. These data, albeit from a cell line, are consistent with observations that MMP-2 was not detected in parenchymal cells in CNS TB suggesting that cell specific down-regulation may be occurring in vivo [31, 32]. Control of MMP-2 activity is usually achieved by restricting the activation of the secreted pro-enzyme . However, in microglial cells decreased MMP-2 secretion was mainly due to inhibition of MMP-2 mRNA accumulation, a phenomenon only previously reported in astrocytoma cells . It is possible that this finding is specific to the CNS immune response.
TNF-α was necessary, but not sufficient for MMP-2 suppression as 50 times the concentration of recombinant molecule was needed to give the equivalent CoMTb effect. We and others have previously demonstrated that TNF-α is often a critical up-regulator of MMP expression and secretion both in TB and other model systems [13, 25, 40]. However, TNF-α has been reported to down-regulate expression and secretion of MMP-2 from both astrocytoma and choroid plexus epithelial cells [43, 44]. In contrast IL-1β had no effect on MMP-2 secretion although in our previous work we demonstrated that this cytokine drives astrocyte MMP-9 secretion . Dexamethasone tends to down-regulate proinflammatory responses and has a clinically important adjuvant role in decreasing inflammation in the treatment of CNS TB . Dexamethasone did not reverse the paradoxical effect of CoMTb on MMP-2 gene expression. Similarly in a rat meningitis model dexamethasone did not influence parenchymal MMP-2 expression suggesting the MMP-2 gene may not be steroid responsive in the CNS .
We investigated the role of ERK and p38 MAP kinase pathways in MMP-2 down-regulation. ERK inhibition further inhibited MMP-2 secretion. In contrast p38 MAP kinase acts as a brake to MMP-2 secretion as pre-incubation of cells with the specific p38 inhibitor SB203580 leading to supra-maximal secretion of MMP-2. The p38 MAP kinase pathway is a critical regulator of inflammatory processes . Our group has demonstrated that p38 acts as a brake in a similar way in pulmonary epithelial cells . To strengthen these in vitro findings, we investigated the expression of phospho-p38 in biopsies from proven human CNS TB patients and showed likely parenchymal activation of this pathway in microglia in vivo for the first time, an important finding from this work. It is not possible using any currently available markers to be certain whether these positive cells were resident microglia or infiltrating peripheral macrophages .
Blockade of the NFκB pathway with SC-514 restored CoMTb inhibited MMP-2 secretion to supra-maximal levels. Similarly, helenalin opposed the effect of CoMTb on MMP-2. Down-regulation of gene expression by the NFκB pathway has been previously described in other secretory pathways, such as apolipoprotein E mRNA in adipocytes via p50 homodimer binding to the promoter, but this is the first time that control of MMP-2 secretion has been shown to be modulated in this way in the CNS [49, 50]. In contrast many other MMP genes are known to have NFκB responsive elements in their promoters that act as up-regulators of gene transcription [51, 52].
Importantly we showed, for the first time, that caspase 8 inhibition restored CoMTb-induced MMP-2 secretion in human microglial cells in a dose dependent fashion independent of the p38 and NFκB pathways. Although p38 signaling was reported as essential for caspase-induced apoptosis in macrophages, we were unable to demonstrate p38 driven caspase 8 activation in our system and blockade did not alter cell numbers . Non-apoptotic roles for caspase 8 including NFκB activation have been described but here caspase 8 blockade had no effect on nuclear recruitment of p50 and p65 NFκB subunits . In contrast caspase 8 may mediate TNF-α activation of NFκB via a p38 independent pathway involving FLICE-associated huge protein (FLASH)-caspase 8 complexes in HeLa and HEK293 cells . Caspase-2 cleavage is also downstream of TNF-α receptor activation and has demonstrated non-apoptotic roles including cell matrix adhesion, as do caspase 3 and 7 [56, 57]. Finally, although caspase 8 activity was demonstrated to be rapidly induced by CoMTb, the effect on MMP-2 secretion was more delayed which suggest that it is probable that there are additional intermediary events occurring in this pathway which are not yet characterized.
In summary, there is a decrease in microglial MMP-2 secretion in response to networks driven by M.tb-infected monocytes, which coupled with the known rise in the acknowledged effector molecule MMP-9 is likely to lead to a change in the CNS inflammatory milieu characterized by alterations in chemokine and cytokine processing as well as cellular migration . Unexpectedly, such networks are paradoxically dependent upon the pro-inflammatory cytokine TNF-α (but not IL-1β). Within microglia, the p38 MAP kinase, NFκB p65 subunits and caspase 8 pathways are all involved in the control of MMP-2 down-regulation. Caspase 8, which to date has been more implicated in regulation of apoptosis in infected cells, acts independently from a separate p38 MAP kinase/NFκB axis to suppress MMP-2 secretion in microglial cells in this simplified cellular model of CNS TB.
JAG was supported the James Maxwell Grant Prophit Tuberculosis Fellowship (Royal College of Physicians London, UK) and by an MRC Clinical Training Fellowship (G0500385). SD was supported by a vacation grant from The Pathology Society, UK. RM is supported by a Wellcome Trust Clinical Research Training Fellowship. JSF & PTE are grateful for support from the NIHR Biomedical Research Centre funding scheme. JSF acknowledges the support of the Imperial College Wellcome Centre for Clinical Tropical Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- CDC: Reported tuberculosis in the United States, 2006. 2007, Atlanta, GA: US Department of Health and Human Services, CDCGoogle Scholar
- Vithalani N, Udani PM: A Study of 292 Autopsy Proven Cases of Tuberculosis. Ind J Tub. 1982, XXIX: 93-97.Google Scholar
- Rich AR, McCordock HA: The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp. 1933, 52.Google Scholar
- Be NA, Kim KS, Bishai WR, Jain SK: Pathogenesis of central nervous system tuberculosis. Curr Mol Med. 2009, 9: 94-99. 10.2174/156652409787581655.PubMed CentralView ArticlePubMedGoogle Scholar
- Parks WC, Wilson CL, Lopez-Boado YS: Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004, 4: 617-629. 10.1038/nri1418.View ArticlePubMedGoogle Scholar
- Murphy G, Knauper V, Atkinson S, Butler G, English W, Hutton M, Stracke J, Clark I: Matrix metalloproteinases in arthritic disease. Arthritis Res. 2002, 4 (Suppl 3): S39-49. 10.1186/ar572.PubMed CentralView ArticlePubMedGoogle Scholar
- Elkington PT, Friedland JS: Matrix metalloproteinases in destructive pulmonary pathology. Thorax. 2005, 61: 259-266.View ArticlePubMedGoogle Scholar
- Newby AC: Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev. 2005, 85: 1-31. 10.1152/physrev.00048.2003.View ArticlePubMedGoogle Scholar
- Opdenakker G, Nelissen I, Van Damme J: Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis. Lancet Neurol. 2003, 2: 747-756. 10.1016/S1474-4422(03)00587-8.View ArticlePubMedGoogle Scholar
- Zhang K, McQuibban GA, Silva C, Butler GS, Johnston JB, Holden J, Clark-Lewis I, Overall CM, Power C: HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci. 2003, 6: 1064-1071. 10.1038/nn1127.View ArticlePubMedGoogle Scholar
- Elkington PT, Nuttall RK, Boyle JJ, O'Kane CM, Horncastle DE, Edwards DR, Friedland JS: Mycobacterium tuberculosis but not vaccine BCG specifically up-regulates matrix metalloproteinase-1. Am J Respir Crit Care Med. 2005, 172: 1596-1604. 10.1164/rccm.200505-753OC.View ArticlePubMedGoogle Scholar
- Harris JE, Nuttall RK, Elkington PT, Green JA, Horncastle DE, Graeber MB, Edwards DR, Friedland JS: Monocyte-astrocyte networks regulate matrix metalloproteinase gene expression and secretion in central nervous system tuberculosis in vitro and in vivo. J Immunol. 2007, 178: 1199-1207.View ArticlePubMedGoogle Scholar
- Price NM, Gilman RH, Uddin J, Recavarren S, Friedland JS: Unopposed matrix metalloproteinase-9 expression in human tuberculous granuloma and the role of TNF-alpha-dependent monocyte networks. J Immunol. 2003, 171: 5579-5586.View ArticlePubMedGoogle Scholar
- Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L: Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium. Science. 2010, 327 (5964): 466-9. 10.1126/science.1179663.PubMed CentralView ArticlePubMedGoogle Scholar
- Friedland JS, Shaw TC, Price NM, Dayer JM: Differential regulation of MMP-1/9 and TIMP-1 secretion in human monocytic cells in response to Mycobacterium tuberculosis. Matrix Biol. 2002, 21: 103-110. 10.1016/S0945-053X(01)00175-5.View ArticlePubMedGoogle Scholar
- Coussens LM, Fingleton B, Matrisian LM: Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002, 295: 2387-2392. 10.1126/science.1067100.View ArticlePubMedGoogle Scholar
- Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T: Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 2003, 253: 269-285. 10.1023/A:1026028303196.View ArticlePubMedGoogle Scholar
- Vincenti MP, Brinckerhoff CE: Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: Can MMPs be good for you?. J Cell Physiol. 2007, 213: 355-364. 10.1002/jcp.21208.View ArticlePubMedGoogle Scholar
- Page-McCaw A, Ewald AJ, Werb Z: Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007, 8: 221-233. 10.1038/nrm2125.PubMed CentralView ArticlePubMedGoogle Scholar
- Harris JE, Fernandez-Vilaseca M, Elkington PT, Horncastle DE, Graeber MB, Friedland JS: IFNgamma synergizes with IL-1beta to up-regulate MMP-9 secretion in a cellular model of central nervous system tuberculosis. FASEB J. 2007, 21: 356-365. 10.1096/fj.06-6925com.View ArticlePubMedGoogle Scholar
- Green JA, Tran CT, Farrar JJ, Nguyen MT, Nguyen PH, Dinh SX, Ho ND, Ly CV, Tran HT, Friedland JS, Thwaites GE: Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis. PLoS One. 2009, 4: e7277-10.1371/journal.pone.0007277.PubMed CentralView ArticlePubMedGoogle Scholar
- Saklatvala J: The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol. 2004, 4: 372-377. 10.1016/j.coph.2004.03.009.View ArticlePubMedGoogle Scholar
- Gebauer F, Hentze MW: Molecular mechanisms of translational control. Nat Rev Mol Cell Biol. 2004, 5: 827-835. 10.1038/nrm1488.View ArticlePubMedGoogle Scholar
- Zebrowski DC, Alcendor RR, Kirshenbaum LA, Sadoshima J: Caspase-3 mediated cleavage of MEKK1 promotes p53 transcriptional activity. J Mol Cell Cardiol. 2006, 40: 605-618. 10.1016/j.yjmcc.2005.11.012.View ArticlePubMedGoogle Scholar
- Zhou M, Zhang Y, Ardans JA, Wahl LM: Interferon-gamma differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis factor-alpha and caspase 8. J Biol Chem. 2003, 278: 45406-45413. 10.1074/jbc.M309075200.View ArticlePubMedGoogle Scholar
- Choi DH, Kim EM, Son HJ, Joh TH, Kim YS, Kim D, Flint Beal M, Hwang O: A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. J Neurochem. 2008, 106: 405-415. 10.1111/j.1471-4159.2008.05399.x.View ArticlePubMedGoogle Scholar
- Overall CM: Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol Biotechnol. 2002, 22: 51-86. 10.1385/MB:22:1:051.View ArticlePubMedGoogle Scholar
- Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, et al: Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet. 2001, 28: 261-265. 10.1038/90100.View ArticlePubMedGoogle Scholar
- Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM: Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med. 2006, 203: 1007-1019. 10.1084/jem.20051342.PubMed CentralView ArticlePubMedGoogle Scholar
- Eugenin EA, Osiecki K, Lopez L, Goldstein H, Calderon TM, Berman JW: CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. J Neurosci. 2006, 26: 1098-1106. 10.1523/JNEUROSCI.3863-05.2006.View ArticlePubMedGoogle Scholar
- Matsuura E, Umehara F, Hashiguchi T, Fujimoto N, Okada Y, Osame M: Marked increase of matrix metalloproteinase 9 in cerebrospinal fluid of patients with fungal or tuberculous meningoencephalitis. J Neurol Sci. 2000, 173: 45-52. 10.1016/S0022-510X(99)00303-2.View ArticlePubMedGoogle Scholar
- Lee KY, Kim EH, Yang WS, Ryu H, Cho SN, Lee BI, Heo JH: Persistent increase of matrix metalloproteinases in cerebrospinal fluid of tuberculous meningitis. J Neurol Sci. 2004, 220: 73-78. 10.1016/j.jns.2004.02.008.View ArticlePubMedGoogle Scholar
- Green JA, Elkington PT, Pennington CJ, Roncaroli F, Dholakia S, Moores RC, Bullen A, Porter JC, Agranoff D, Edwards DR, Friedland JS: Mycobacterium tuberculosis upregulates microglial matrix metalloproteinase-1 and -3 expression and secretion via NF-kappaB- and Activator Protein-1-dependent monocyte networks. J Immunol. 2010, 184: 6492-6503. 10.4049/jimmunol.0903811.View ArticlePubMedGoogle Scholar
- Elkington PT, Green JA, Friedland JS: Filter sterilization of highly infectious samples to prevent false negative analysis of matrix metalloproteinase activity. J Immunol Methods. 2006, 309: 115-119. 10.1016/j.jim.2005.11.010.View ArticlePubMedGoogle Scholar
- Leber TM, Balkwill FR: Zymography: a single-step staining method for quantitation of proteolytic activity on substrate gels. Anal Biochem. 1997, 249: 24-28. 10.1006/abio.1997.2170.View ArticlePubMedGoogle Scholar
- Snoek-van Beurden PA, Von den Hoff JW: Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. Biotechniques. 2005, 38: 73-83. 10.2144/05381RV01.View ArticlePubMedGoogle Scholar
- Elkington PT, Green JA, Emerson JE, Lopez-Pascua LD, Boyle JJ, O'Kane CM, Friedland JS: Synergistic up-regulation of epithelial cell matrix metalloproteinase-9 secretion in tuberculosis. Am J Respir Cell Mol Biol. 2007, 37: 431-437. 10.1165/rcmb.2007-0011OC.View ArticlePubMedGoogle Scholar
- Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987, 162: 156-159.View ArticlePubMedGoogle Scholar
- Nuttall RK, Pennington CJ, Taplin J, Wheal A, Yong VW, Forsyth PA, Edwards DR: Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. Mol Cancer Res. 2003, 1: 333-345.PubMedGoogle Scholar
- Elkington PT, Emerson JE, Lopez-Pascua LD, O'Kane CM, Horncastle DE, Boyle JJ, Friedland JS: Mycobacterium tuberculosis Up-Regulates Matrix Metalloproteinase-1 Secretion from Human Airway Epithelial Cells via a p38 MAPK Switch. J Immunol. 2005, 175: 5333-5340.View ArticlePubMedGoogle Scholar
- Wickremasinghe MI, Thomas LH, Friedland JS: Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network. J Immunol. 1999, 163: 3936-3947.PubMedGoogle Scholar
- O'Kane CM, Elkington PT, Friedland JS: Monocyte-dependent oncostatin M and TNF-alpha synergize to stimulate unopposed matrix metalloproteinase-1/3 secretion from human lung fibroblasts in tuberculosis. Eur J Immunol. 2008, 38: 1321-1330. 10.1002/eji.200737855.View ArticlePubMedGoogle Scholar
- Qin H, Moellinger JD, Wells A, Windsor LJ, Sun Y, Benveniste EN: Transcriptional suppression of matrix metalloproteinase-2 gene expression in human astroglioma cells by TNF-alpha and IFN-gamma. J Immunol. 1998, 161: 6664-6673.PubMedGoogle Scholar
- Zeni P, Doepker E, Schulze-Topphoff U, Huewel S, Tenenbaum T, Galla HJ: MMPs contribute to TNF-alpha-induced alteration of the blood-cerebrospinal fluid barrier in vitro. Am J Physiol Cell Physiol. 2007, 293: C855-864. 10.1152/ajpcell.00470.2006.View ArticlePubMedGoogle Scholar
- Harris JE, Green JA, Elkington PT, Friedland JS: Monocytes infected with Mycobacterium tuberculosis regulate MAP kinase-dependent astrocyte MMP-9 secretion. J Leukoc Biol. 2006, 81: 548-556.View ArticlePubMedGoogle Scholar
- Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, Nguyen QH, Nguyen TT, Nguyen NH, Nguyen TN, et al: Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004, 351: 1741-1751. 10.1056/NEJMoa040573.View ArticlePubMedGoogle Scholar
- Liu X, Han Q, Sun R, Li Z: Dexamethasone regulation of matrix metalloproteinase expression in experimental pneumococcal meningitis. Brain Res. 2008, 1207: 237-243.View ArticlePubMedGoogle Scholar
- Prinz M, Mildner A: Microglia in the CNS: Immigrants from Another World. Glia. 2011, 59: 177-187. 10.1002/glia.21104.View ArticlePubMedGoogle Scholar
- Grempler R, Kienitz A, Werner T, Meyer M, Barthel A, Ailett F, Sutherland C, Walther R, Schmoll D: Tumour necrosis factor alpha decreases glucose-6-phosphatase gene expression by activation of nuclear factor kappaB. Biochem J. 2004, 382: 471-479. 10.1042/BJ20040160.PubMed CentralView ArticlePubMedGoogle Scholar
- Yue L, Christman JW, Mazzone T: Tumor necrosis factor-alpha-mediated suppression of adipocyte apolipoprotein E gene transcription: primary role for the nuclear factor (NF)-kappaB pathway and NFkappaB p50. Endocrinology. 2008, 149: 4051-4058. 10.1210/en.2008-0340.PubMed CentralView ArticlePubMedGoogle Scholar
- Lu Y, Wahl LM: Production of matrix metalloproteinase-9 by activated human monocytes involves a phosphatidylinositol-3 kinase/Akt/IKKalpha/NF-kappaB pathway. J Leukoc Biol. 2005, 78: 259-265. 10.1189/jlb.0904498.View ArticlePubMedGoogle Scholar
- Chase AJ, Bond M, Crook MF, Newby AC: Role of nuclear factor-kappa B activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arterioscler Thromb Vasc Biol. 2002, 22: 765-771. 10.1161/01.ATV.0000015078.09208.92.View ArticlePubMedGoogle Scholar
- Park MT, Choi JA, Kim MJ, Um HD, Bae S, Kang CM, Cho CK, Kang S, Chung HY, Lee YS, Lee SJ: Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem. 2003, 278: 50624-50634. 10.1074/jbc.M309011200.View ArticlePubMedGoogle Scholar
- Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P: Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 2007, 14: 44-55. 10.1038/sj.cdd.4402047.View ArticlePubMedGoogle Scholar
- Jun JI, Chung CW, Lee HJ, Pyo JO, Lee KN, Kim NS, Kim YS, Yoo HS, Lee TH, Kim E, Jung YK: Role of FLASH in caspase-8-mediated activation of NF-kappaB: dominant-negative function of FLASH mutant in NF-kappaB signaling pathway. Oncogene. 2005, 24: 688-696. 10.1038/sj.onc.1208186.View ArticlePubMedGoogle Scholar
- Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B: Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011, 472 (7343): 319-24. 10.1038/nature09788.View ArticlePubMedGoogle Scholar
- Manzl C, Krumschnabel G, Bock F, Sohm B, Labi V, Baumgartner F, Logette E, Tschopp J, Villunger A: Caspase-2 activation in the absence of PIDDosome formation. J Cell Biol. 2009, 185: 291-303. 10.1083/jcb.200811105.PubMed CentralView ArticlePubMedGoogle Scholar
- Opdenakker G, Van den Steen PE, Van Damme J: Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol. 2001, 22: 571-579. 10.1016/S1471-4906(01)02023-3.View ArticlePubMedGoogle Scholar
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