<i>Mycobacterium tuberculosis</i> Up-Regulates Matrix Metalloproteinase-1 Secretion from Human Airway Epithelial Cells via a p38 MAPK Switch

Elkington, Paul; Emerson, Jenny E.; Lopez-Pascua, Laura D. C.; O’Kane, Cecilia; Horncastle, Donna; Boyle, Joseph J.; Friedland, Jon S.

doi:10.4049/jimmunol.175.8.5333

Cited by 111 publications

(143 citation statements)

References 52 publications

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“…Expression of TIMP-2 and TIMP-3 has been shown to decrease during M. tuberculosis infection of human macrophages, while TIMP-1 expression is suppressed by M. tuberculosis in human pulmonary epithelial cells. 4,9 The regulation of MMP and TIMP expression is complex and not yet fully understood. The anti-inflammatory cytokine interleukin-10 (IL-10) has previously been reported to inhibit mononuclear phagocyte MMP-1, MMP-7 and MMP-9 secretion and to induce TIMP-1 expression.…”

Section: Discussionmentioning

confidence: 99%

1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

et al. 2009

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Summary Matrix metalloproteinases (MMP) can degrade all components of pulmonary extracellular matrix. Mycobacterium tuberculosis induces production of a number of these enzymes by human macrophages, and these are implicated in the pathogenesis of pulmonary cavitation in tuberculosis. The active metabolite of vitamin D, 1α,25‐dihydroxyvitamin D3 [1α,25(OH)2D3], has previously been reported to inhibit secretion of MMP‐9 in human monocytes (MN), but its influence on the secretion and gene expression of MMP and tissue inhibitors of MMP (TIMP) in M. tuberculosis‐infected cells has not previously been investigated. We therefore determined the effects of 1α,25(OH)2D3 on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis‐infected human leucocytes; we also investigated the effect of 1α,25(OH)2D3 on the secretion of interleukin‐10 (IL‐10) and prostaglandin E2 (PGE2), both transcriptional regulators of MMP expression. We found that M. tuberculosis induced expression of MMP‐1, MMP‐7 and MMP‐10 in MN and MMP‐1 and MMP‐10 in peripheral blood mononuclear cells (PBMC). 1α,25(OH)2D3 significantly attenuated M. tuberculosis‐induced increases in expression of MMP‐7 and MMP‐10, and suppressed secretion of MMP‐7 by M. tuberculosis‐infected PBMC. MMP‐9 gene expression, secretion and activity were significantly inhibited by 1α,25(OH)2D3 irrespective of infection. In contrast, the effects of 1α,25(OH)2D3 on the expression of TIMP‐1, TIMP‐2 and TIMP‐3 and secretion of TIMP‐1 and TIMP‐2 were small and variable. 1α,25(OH)2D3 also induced secretion of IL‐10 and PGE2 from M. tuberculosis‐infected PBMC. These findings represent a novel immunomodulatory role for 1α,25(OH)2D3 in M. tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

et al. 2009

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“…Monocytes were isolated from single-donor buffy coats (National Blood Transfusion Service, Collindale, UK) or whole blood from healthy volunteers as previously described [9]. Monocytes were isolated from at least six different donors.…”

Section: Monocyte Isolation and Infection With Mtbmentioning

confidence: 99%

“…MMP-1 (interstitial collagenase) is the most abundant pulmonary enzyme capable of degrading type I collagen [5]. Several cell types secrete MMP-1 in TB [9,10] but there are no data on the role of fibroblast-derived MMP-1 in TB. However, stimulated fibroblasts are the most potent source of MMP-1 in the lung [11] and may cause type IV collagen and proteoglycan degradation via MMP-3 secretion.…”

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confidence: 99%

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

2008

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Leukocyte-derived matrix metalloproteinases (MMP) are implicated in the tissue destruction characteristic of tuberculosis (TB). The contribution of lung stromal cells to MMP activity in TB is unknown. Oncostatin M (OSM) is an important stimulus to extrapulmonary stromal MMP induction, but its role in regulation of pulmonary MMP secretion or pathophysiology of TB is unknown. We investigated OSM secretion from Mycobacterium tuberculosis (Mtb)-infected human monocytes/macrophages and the networking effects of such OSM on lung fibroblast MMP secretion. Mtb increased monocyte OSM secretion dose dependently in vitro. In vivo tuberculous granulomas immunostained positively for OSM. Further, conditioned media from Mtb-infected monocytes (CoMTb) induced monocyte OSM secretion (670 AE 55 versus 166 AE 14 pg/mL in controls), implicating an autocrine loop. Mtbinduced OSM secretion was prostaglandin (PG) sensitive, and required activation of surface G-protein coupled receptors. OSM induction was ERK MAP kinase dependent, p38-requiring but JNK-independent. OSM synergized with TNF-a, a key cytokine in TB granuloma formation, to stimulate pulmonary fibroblast MMP-1/-3 secretion, while suppressing secretion of tissue inhibitors of metalloproteinases-1/-2. In summary, Mtb infection of monocytes results in PG-dependent OSM secretion, which synergizes with TNF-a to drive functionally unopposed fibroblast MMP-1/-3 secretion, demonstrating a previously unrecognized role for OSM in TB.Key words: Human Á Inflammation Á Monocytes/macrophages Á Stromal cells Introduction Tuberculosis (TB) remains a major global health problem with over 8 million cases of overt clinical infection, and 2 million deaths annually. The pathological response to Mycobacterium tuberculosis (Mtb) infection is characterised by extensive tissue breakdown including caseous necrosis, and later fibrosis. Tissue destruction in TB requires degradation of matrix proteins including collagen and elastin, and several studies have implicated matrix metalloproteinases (MMP) in pathogenesis [1][2][3]. MMP are a group of 23 related zinc-dependent enzymes that together are capable of degrading all components of the extracellular matrix (ECM) [4]. MMP are inhibited in vivo by the tissue inhibitors of metalloproteinases (TIMP), and in general, overall proteolytic activity is determined by the molar ratio of MMP:TIMP. MMP secretion is induced by inflammatory cytokines, physical stimuli, or directly by some bacterial components [5]. Direct infection of mononuclear cells with Mtb has been shown to induce MMP-9 (gelatinase B), a process that depends in part on 6].In the lung, the principal structural supporting collagen is type I [7,8]. MMP-1 (interstitial collagenase) is the most abundant pulmonary enzyme capable of degrading type I collagen [5]. Several cell types secrete MMP-1 in TB [9,10] but there are no data on the role of fibroblast-derived MMP-1 in TB. However, stimulated fibroblasts are the most potent source of MMP-1 in the lung [11] and may cause type IV collagen and prote...

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“…The virulent Mtb strain H37Rv Pasteur was cultured in 7H9 broth supplemented with ADC enrichment medium as previously described (29).…”

Section: Mtb Culturementioning

confidence: 99%

Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages

O’Kane

Boyle

Horncastle

et al. 2007

The Journal of Immunology

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CXCL8 is a chemokine that is implicated in the formation of tuberculous (TB) granulomas and in immunity to Mycobacterium tuberculosis (Mtb). Fibroblast chemokine secretion is important for modulating inflammatory responses in chronic lung disease and inflammatory arthritis but has not been investigated in the pathophysiology of TB. In this study, we used a cellular model to examine monocyte/macrophage-dependent stimulation of fibroblasts by Mtb in the regulation of chemokine secretion, particularly that of CXCL8. Human lung fibroblasts grown in collagen were stimulated with conditioned medium from Mtb-infected monocytes (CoMTb). CoMTb-induced prolonged dose-dependent, p38-mediated expression of stable CXCL8 mRNA by fibroblasts accompanied by a >10-fold increase in CXCL8 secretion (487 ± 88 ng/ml vs 48.6 ± 34 ng/ml in controls) at 120 h. Fibroblasts strongly expressed CXCL8 in vivo in human TB granulomas. Inhibition of TNF-α or IL-1 in CoMTb abrogated the induction of CXCL8 at a pretranscriptional level. CXCL8 secretion was NF-κB, C/EBP, and JNK dependent. Sustained NF-κB activation was demonstrated beyond 24 h in response to CoMTb. Exogenous CXCL8 reduced the survival of Mtb within macrophages, and inhibition of CXCL8 was associated with intracellular mycobacterial proliferation. These data show that fibroblasts have a previously unrecognized role in modulating inflammation in TB by their CXCL8-dependent contribution to cell recruitment and mycobacterial killing within the granuloma.

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Mycobacterium tuberculosis Up-Regulates Matrix Metalloproteinase-1 Secretion from Human Airway Epithelial Cells via a p38 MAPK Switch

Cited by 111 publications

References 52 publications

1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages

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Mycobacterium tuberculosis Up-Regulates Matrix Metalloproteinase-1 Secretion from Human Airway Epithelial Cells via a p38 MAPK Switch

Cited by 111 publications

References 52 publications

1α,25‐dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

1α,25‐dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages

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1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection