CD147 Is a Signaling Receptor for Cyclophilin B

Yurchenko, Vyacheslav; O’Connor, Matthew; Dai, Wei; Guo, Huiming; Toole, Bryan P.; Sherry, Barbara; Bukrinsky, Michael

doi:10.1006/bbrc.2001.5847

Cited by 131 publications

(125 citation statements)

References 18 publications

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“…CD147 is a type I transmembrane glycoprotein, a member of the immunoglobulin super-family, that is expressed by a wide array of cell types, including epithelial, endothelial and hematopoietic cells (6). CD147 is a signaling receptor for extracellular cyclophilins (Cyp) A and B (7,8), and recent publications have identified the CD147 signaling pathway induced by extracellular cyclophilins as a triggering mechanism regulating MMP expression and inflammation in atherosclerosis, rheumatoid arthritis, allergic and chronic lung disease (9)(10)(11)(12)(13)(14). Thus, we hypothesized that CD147 activation by extracellular cyclophilin may play a role in experimental BA as well.…”

Section: Targeting Extracellular Cyclophilins Ameliorates Disease Promentioning

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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Section: Targeting Extracellular Cyclophilins Ameliorates Disease Promentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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“…Importantly, it is released intact by heparanase and matrix metalloproteinases (MMPs), suggesting that it can participate in tissue inflammation. Both CyPA and CyPB exhibit potent chemotactic properties in vitro and in vivo, indicating that they contribute to leukocyte infiltration during the acute phase of inflammation (14,(19)(20)(21)(22). CD147, also known as an extracellular MMP inducer, was demonstrated to act as a signaling receptor for extracellular cyclophilins and mediate their chemotactic activity via a mechanism involving Ca 2+ mobilization and p44/p42 MAPK activation (19,20).…”

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confidence: 99%

Cyclophilin B Attenuates the Expression of TNF-α in Lipopolysaccharide-Stimulated Macrophages through the Induction of B Cell Lymphoma-3

Marcant

Denys

Melchior

et al. 2012

The Journal of Immunology

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Extracellular cyclophilin A (CyPA) and CyPB have been well described as chemotactic factors for various leukocyte subsets, suggesting their contribution to inflammatory responses. Unlike CyPA, CyPB accumulates in extracellular matrixes, from which it is released by inflammatory proteases. Hence, we hypothesized that it could participate in tissue inflammation by regulating the activity of macrophages. In the current study, we confirmed that CyPB initiated in vitro migration of macrophages, but it did not induce production of proinflammatory cytokines. In contrast, pretreatment of macrophages with CyPB attenuated the expression of inflammatory mediators induced by LPS stimulation. The expression of TNF-α mRNA was strongly reduced after exposure to CyPB, but it was not accompanied by significant modification in LPS-induced activation of MAPK and NF-κB pathways. LPS activation of a reporter gene under the control of TNF-α gene promoter was also markedly decreased in cells treated with CyPB, suggesting a transcriptional mechanism of inhibition. Consistent with this hypothesis, we found that CyPB induced the expression of B cell lymphoma-3 (Bcl-3), which was accompanied by a decrease in the binding of NF-κB p65 to the TNF-α promoter. As expected, interfering with the expression of Bcl-3 restored cell responsiveness to LPS, thus confirming that CyPB acted by inhibiting initiation of TNF-α gene transcription. Finally, we found that CyPA was not efficient in attenuating the production of TNF-α from LPS-stimulated macrophages, which seemed to be due to a modest induction of Bcl-3 expression. Collectively, these findings suggest an unexpected role for CyPB in attenuation of the responses of proinflammatory macrophages.

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“…The resorption process of organic matrix is undertaken by MMPs (Kim et al, 2008a). Cyp-A is internalized by binding to the glycosylated cell surface receptor known as an EMM-PRIN or basigin, neurothelin, or CD147 (Yurchenko et al, 2001). This receptor is involved in MMPs expression (Sameshima et al, 2000;Li et al, 2001) and regulates MMP production via the MAPK pathway (Lai et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The secreted form of Cyp-A is a potent chemoattractant for monocytes and macrophages (Pan et al, 2008;Payeli et al, 2008;Damsker, 2009), which become fused to form osteoclasts that are essential for preparing an eruptive pathway of the tooth germ. Moreover, Cyp-A is internalized by binding to a cell surface receptor, known as an extracellular matrix metalloproteinase inducer (EMMPRIN; Yurchenko et al, 2001). This receptor is involved in the expression of matrix metalloproteinase proteins (MMPs), which are essential for matrix maturation in dental hard tissue (Sameshima et al, 2000;Li et al, 2001;Xie et al, 2010).…”

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confidence: 99%

Differential Expression of Cyclophilin A and EMMPRIN in Developing Molars of Rats

Yang

Park

Kim

et al. 2011

The Anatomical Record

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A complex and intricate cascade of gene expression is essential for late stage tooth development. This study was performed to detect molecules involved in dental hard tissue formation and tooth eruption by comparing gene expression in cap stage molar germs (before eruptive movement and dental hard tissue formation) with that in root formation stage molar germs (after eruptive movement and dental hard tissue formation). DD-PCR revealed that cyclophilin A (Cyp-A), a potent chemoattractant for monocytes as well as a ligand for extracellular matrix metalloproteinase inducer (EMMPRIN) was expressed differentially in the two stages molar germs. The levels of Cyp-A and EMMPRIN mRNA were significantly higher at the root formation stage than at the cap and crown stages of the molar germs. Immunofluorescence showed that Cyp-A and EMMPRIN were expressed strongly in the follicular cells overlaying the occlusal region of the molar germs at the root formation stage. In contrast, their immunoreactivity was weak in the follicular tissues and was not region-specific in molar germs at the cap stage. In addition, the MCP-1 and CSF-1 mRNA levels increased in parallel to that of Cyp-A mRNA and the increased number of osteoclasts at the occlusal region. Immunoreactivity against Cyp-A and EMMPRIN was also observed in the fully differentiated ameloblasts and odontoblasts. This study suggests that Cyp-A and EMMPRIN play roles in the maturation of dental hard tissue and the formation of an eruption pathway. Anat Rec, 295:150-159, 2012. V V C 2011 Wiley Periodicals, Inc.

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CD147 Is a Signaling Receptor for Cyclophilin B

Cited by 131 publications

References 18 publications

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Cyclophilin B Attenuates the Expression of TNF-α in Lipopolysaccharide-Stimulated Macrophages through the Induction of B Cell Lymphoma-3

Differential Expression of Cyclophilin A and EMMPRIN in Developing Molars of Rats

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