Cytokine synergy, collagenases and cartilage collagen breakdown

2003 ◽  
Vol 70 ◽  
pp. 125-133 ◽  
Author(s):  
Tim E. Cawston ◽  
Jenny M. Milner ◽  
Jon B. Catterall ◽  
Andrew D. Rowan
Keyword(s):  
Matrix Metalloproteinases ◽  
Inflammatory Cytokines ◽  
Activator Protein 1 ◽  
Activator Protein ◽  
And Cartilage ◽  
Pro Inflammatory Cytokines

We have investigated proteinases that degrade cartilage collagen. We show that pro-inflammatory cytokines act synergistically with oncastatin M to promote cartilage collagen resorption by the up-regulation and activation of matrix metalloproteinases (MMPs). The precise mechanisms are not known, but involve the up-regulation of c-fos, which binds to MMP promoters at a proximal activator protein-1 (AP-1) site. This markedly up-regulates transcription and leads to higher levels of active MMP proteins.

scholarly journals Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 442
Author(s):  
Hany H. Arab ◽  
Ahmed M. Ashour ◽  
Abdulmalik M. Alqarni ◽  
El-Shaimaa A. Arafa ◽  
Ahmed M. Kabel
Keyword(s):  
Matrix Metalloproteinases ◽  
Inflammatory Cytokines ◽  
Renal Damage ◽  
Mapk Pathway ◽  
Antioxidant Properties ◽  
Kidney Tissue ◽  
Camel Milk ◽  
Renal Inflammation ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Renal damage is a devastating adverse effect for cyclosporine; a widely used immunosuppressant drug. The present work examined the potential of camel milk, a natural agent with marked anti-inflammatory/antioxidant properties, to attenuate cyclosporine-induced renal injury. The kidney tissue was examined with the aid of Western blotting, immunohistochemistry, biochemical assays, including colorimetric and ELISA kits. The present findings revealed that camel milk (10 mL/kg/day; for 3 weeks by gavage) significantly lowered serum creatinine, BUN, and KIM-1 renal dysfunction markers. Mechanistically, camel milk inhibited renal inflammation, as seen by significant decrease of the pro-inflammatory cytokines (MCP-1, TNF-α, IL-1β, and IL-18) and extracellular degradation signals (MMP-2 and MMP-9) and enhanced the generation of the anti-inflammatory IL-10. Moreover, it inhibited the upstream pro-inflammatory p38/ERK/JNK MAPK pathway by lowering the phosphorylation of the 3 subfamilies of MAPKs (p38 MAPK, JNK1/2, and ERK1/2). Furthermore, camel milk curbed the NF-κB pathway activation by downregulating the protein expression of activated NF-κBp65, p-NF-κBp65, and p-IκBα proteins. Additionally, camel milk inhibited renal oxidative stress by lowering the MPO activity and augmenting the reduced/oxidized glutathione ratio and total antioxidant capacity. These findings propose that camel milk may be a promising agent that inhibits cyclosporine-triggered renal inflammation via curtailing the p38/ERK/JNK MAPK and NF-κB pathways, matrix metalloproteinases, and pro-inflammatory cytokines.

scholarly journals Treponema denticola dentilisin triggered TLR2/MyD88 activation upregulates a tissue destructive program involving MMPs via Sp1 in human oral cells

2021 ◽  
Author(s):  
Sean Ganther ◽  
Allan Radaic ◽  
Nick Chang ◽  
Christian Tafolla ◽  
Ling Zhan ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Periodontal Disease ◽  
Disease Progression ◽  
Inflammatory Cytokines ◽  
Oral Microbiome ◽  
Treponema Denticola ◽  
Periodontal Tissue ◽  
Cellular Processes ◽  
Pro Inflammatory Cytokines

ABSTRACTPeriodontal disease is driven by dysbiosis of the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola, is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed a significant upregulation of genes associated with extracellular matrix organization and degradation, including tissue-specific inducible MMPs that may play novel roles in modulating host immune responses yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula, failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of either TLR2 or MyD88 abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs, whereas a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola-mediated activation of TLR2/MyD88 led to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola-dependent MMP expression. Taken together, these data support that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.AUTHOR SUMMARYPeriodontal disease is driven by dysbiosis of the oral microbiome, which interacts with host tissues and thereby induces the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs), leading to destruction of the periodontal tissues. Even after clinical intervention, patients with severe periodontal disease are left with a persistent pro-inflammatory transcriptional profile throughout the periodontium. The oral spirochete, Treponema denticola, is consistently found at elevated levels in periodontal lesions and is associated with several pathophysiological effects driving periodontal disease progression. The T. denticola surface-expressed protease complex (dentilisin) has cytopathic effects consistent with periodontal disease pathogenesis. To date, few direct links have been reported between dentilisin and the cellular and tissue processes that drive periodontal tissue destruction at the transcriptional and/or epigenetic levels. Here, we utilize wild type and dentilisin-deficient T. denticola as well as purified dentilisin to characterize dentilisin-dependent activation of intracellular pathways controlling MMP expression and activity. Our results define a role for dentilisin in initiating this signal cascade. Also, our study identified tissue-specific inducible MMPs that may play novel roles in modulating as-yet uncharacterized host responses in periodontal disease. Lastly, T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion. Taken together, our study provides new insights into the molecular mechanisms underpinning periodontal disease progression which could lead to the development of more efficacious therapeutic treatments.

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