STAT3, p38 MAPK, and NF-κB Drive Unopposed Monocyte-Dependent Fibroblast MMP-1 Secretion in Tuberculosis

O'Kane, Cecilia M; Elkington, Paul; Jones, Michael D.; Caviedes, Luz; Tovar, Marco A.; Gilman, Robert H.; Stamp, Gordon W.; Friedland, Jon S.

doi:10.1165/rcmb.2009-0211oc

Cited by 67 publications

(79 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite a positive correlation between MAPK/p38 activation and REGg overexpression, JNK activation is not observed following TPA stimulation in our study, indicating some specificity in the transduction of TPA-induced carcinogenic signals 26 . A similar phenomenon has been reported; MMP-1 upregulation and TIMP-1 downregulation are p38 (but not ERK or JNK) MAPK-dependent 27 . This is the first study demonstrating that the MAPK/p38 signalling pathway is involved in the regulation of REGg expression.…”

Section: Discussionsupporting

confidence: 84%

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Dang

Zhang

et al. 2015

Nat Commun

View full text Add to dashboard Cite

Here we report that mice deficient for the proteasome activator, REGg, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGg in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGg elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGg promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGg activates Wnt/b-catenin signalling by degrading GSK-3b in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of b-catenin. Conversely, MAPK/p38 inactivation or REGg deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGg acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/b-catenin pathway.

show abstract

Section: Discussionsupporting

confidence: 84%

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Dang

Zhang

et al. 2015

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Since stromal cells are more numerous in the lung and may express relatively greater levels of MMPs than monocytic cells [61], they represent a potentially important source of MMPs in TB. Monocyteepithelilal cell networks upregulate MMP-1 and -9 [35,36], while monocyte-fibroblast networks upregulate MMP-1 and -3 [62,63]. In our cellular model of TB meningitis, monocyteastrocyte networks were found to upregulate MMP-1, -2, -3, -7 and -9 gene expression [41].…”

Section: Mmps Driven By Intercellular Networkmentioning

confidence: 69%

“…Both the p38 and extracellular signal-related kinase/mitogenactivated protein kinase (MAPK) pathways are critical in regulating MMP secretion in multiple cell types, both as a result of direct infection and intercellular networks [35,36,63,66,67]. Although p38 MAPK pathway activation has multiple effects, including mRNA stabilisation, in primary human macrophages one critical downstream effector is the cyclooxygenase (COX) pathway.…”

Section: Regulation Of Mmp Expressionmentioning

confidence: 99%

See 1 more Smart Citation

Matrix metalloproteinases in tuberculosis

Elkington¹,

Ugarte-Gil²,

Friedland³

2011

European Respiratory Journal

114

View full text Add to dashboard Cite

Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.

show abstract

“…No significant cell death was observed with the concentrations of inhibitors used. NF-kB regulates gene expression of diverse MMPs, including collagenases in TB (34,35). MMP-10 does not have a consensus NF-kB binding site in its promoter, although NF-kB noncanonical promoter binding was shown to occur in the promoter of the related stromelysin MMP-3 (36).…”

Section: Mmp-10 Secretion From Mtbstimulated Macrophages Is Mapk Depementioning

confidence: 99%

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

Brilha

Sathyamoorthy

Stuttaford

et al. 2017

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Tuberculosis (TB) causes disease worldwide, and multidrug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction, which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb)-infected macrophages and in conditioned medium from Mtb-infected monocyte-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, whereas Mtb-infected monocytes increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of patients with TB from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared with control subjects and patients with other respiratory diseases (both P , 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette-Guerin (P , 0.001), whereas both mycobacteria up-regulated TNF-a secretion equally. Using overlapping, short, linear peptides covering the sequence of early secretory antigenic target-6, a virulence factor secreted by Mtb, but not bacillus Calmette-Guerin, we found that stimulation of human macrophages with a single specific 15-amino acid peptide sequence drove threefold greater MMP-10 secretion than any other peptide (P , 0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and extracellular signal-related kinase mitogen-activated protein kinase blockade (P , 0.001 and P , 0.01 respectively), but it was not affected by inhibition of NF-kB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction.

show abstract

STAT3, p38 MAPK, and NF-κB Drive Unopposed Monocyte-Dependent Fibroblast MMP-1 Secretion in Tuberculosis

Cited by 67 publications

References 35 publications

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Matrix metalloproteinases in tuberculosis

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

Contact Info

Product

Resources

About