Dealing with the family: CD147 interactions with cyclophilins

Yurchenko, Vyacheslav; Constant, Stephanie L.; Bukrinsky, Michael

doi:10.1111/j.1365-2567.2005.02316.x

Cited by 166 publications

(162 citation statements)

References 97 publications

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“…Therefore, we choose this protein as a potential therapeutic target. Yeast two hybrid studies identified CD147 as an extracellular receptor for cyclophilin and further studies demonstrated that this receptor mediates the pro-inflammatory actions of cyclophilin (16). In our study when we inhibited CD147 we significantly reduced sepsis-induced renal injury.…”

Section: Discussionsupporting

confidence: 49%

“…These tissue changes were validated by western blot. Recent studies have demonstrated that extracellular cyclophilin is proinflammatory via the CD147 receptor and that anti-CD147 antibodies are anti-inflammatory (12,13,14,15,16). Administration of anti-CD147 antibodies significantly reduced sepsis-induced acute renal failure and reduced both pro and anti inflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

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Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Dear

Leelahavanichkul

Aponte

et al. 2007

Critical Care Medicine

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Objective-Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and, therefore, identify new drug targets. Design-Proteomic discovery study and drug target validation Setting-Research institute laboratorySubjects-Three month old C57BL/6 mice Interventions-We used a mouse model of sepsis based on cecal ligation and puncture (CLP) but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in-gel electrophoresis (DIGE). We compared liver proteins from 6 hr post-CLP to shamoperated mice ('early proteins') and 24 hr post-CLP with 6 hr post-CLP ('late proteins'). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction.Results-The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase proteins, coagulation, ER stress, oxidative stress, apoptosis, mitochondrial proteins and nitric oxide metabolism. We found that cyclophilin increased in abundance after CLP. When the receptor for this protein, CD147, was inhibited sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited.Conclusion-By applying proteomics to a clinically relevant mouse model of sepsis we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Dear

Leelahavanichkul

Aponte

et al. 2007

Critical Care Medicine

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“…We found that MM284 administration also reduced mRNA expression of a number of proinflammatory mediators downstream from SMAD2 activation, which was also inhibited, suggesting that extracellular cyclophilin plays a role in the inflammation associated with this model of BA. Given that the major signaling receptor for extracellular cyclophilins is CD147 (30), our data suggest that interaction between extracellular cyclophilins and CD147 plays a significant role in inflammation and hepatic pathology in experimental BA. Indeed, several reports have demonstrated activation of the CD147-induced signaling pathways by CypA circulating in extracellular media in a number of inflammatory diseases (31).…”

Section: Discussionmentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.

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“…It is expressed by many types of cells, including hematopoietic, epithelial, endothelial, and tumor cells. 12,13 It is well documented that Bsg induces MMPs, so it is also known as an extracellular matrix metalloproteinase inducer (EMMPRIN). 14 It is highly up-regulated in many malignant cancer cells and is thought to contribute to cell survival, invasion, metastasis, and multidrug resistance.…”

mentioning

confidence: 99%

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

Kato

Kosugi

Sato

et al. 2011

The American Journal of Pathology

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Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/ CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg ؊/؊ ) demonstrated significantly less fibrosis after surgery than Bsg ؉/؉ mice. Fewer macrophages had infiltrated in Bsg ؊/؊ kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg ؊/؊ mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor ␤. Furthermore, Bsg ؊/؊ embryonic fibro blasts produced less hyaluronan and ␣-smooth muscle actin after transforming growth factor ␤ stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis.

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Dealing with the family: CD147 interactions with cyclophilins

Cited by 166 publications

References 97 publications

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

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