Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages

Kim, Ho; Kim, Wonjung; Jeon, Sung-Tak; Koh, Eun‐Mi; Cha, Hoon‐Suk; Ahn, Kwang‐Soon; Lee, Won‐Ha

doi:10.1016/j.clim.2005.05.004

Cited by 124 publications

(123 citation statements)

References 26 publications

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“…The decreased migration of neutrophils and other inflammatory cells to the liver may explain the decreased levels of IL-6 observed in MM284-treated animals in our study. Downregulation of IL-6 by MM284 is consistent with previous reports demonstrating induction of IL-6, IL-8, IL-1β, MCP-1 and tumor necrosis factor (TNF)-α in monocytes by extracellular CypA (24,25). Another cell type likely contributing to disease pathogenesis are HSCs, as our data showed activation of SMAD2 in human HSCs after CypA exposure and inhibition of this effect by MM284 treatment, mimicking the effects observed with whole liver.…”

Section: Discussionsupporting

confidence: 92%

“…IL-6 is a multifunctional cytokine that is implicated in the pathogenesis of multiple diseases associated with inflammation, including inflammatory liver diseases, and is known to be secreted by macrophages in response to extracellular cyclophilin (24,25). Thus, we next investigated whether MM284 had an effect on IL-6 production in our model.…”

Section: Mm284 Reduces Interleukin (Il)-6 Mrna Expression In the Livementioning

confidence: 99%

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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: Discussionsupporting

confidence: 92%

Section: Mm284 Reduces Interleukin (Il)-6 Mrna Expression In the Livementioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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“…CyPA was reported to induce the production of proinflammatory cytokines and chemokines, such as TNF-a, IL-1b, IL-6, CXCL8/IL-8, and CCL2/MCP-1 (23). However, these findings are in contradiction with other studies, which demonstrated that the levels of proinflammatory mediators were either undetectable or very low, but without any comparison with those obtained with TLR agonists (24)(25)(26).…”

mentioning

confidence: 68%

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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“…In their immunohistochemical investigation of synovial fluid from patients with rheumatoid arthritis, Ho Kim et al detected cyclophilin A in endothelial cells, particularly macrophages, lymphocytes, and smooth muscle cells. (14). A study by Satoh et al (16), support the idea that cyclophilin A levels increases during inflammatory processes.…”

Section: Discussionmentioning

confidence: 88%

“…Cyclophilin A induces the formation of adhesion molecules from endothelial cells and causes övascular smooth muscle cells to multiply and migrate (4). Cyclophilin A is also involved in the activation of matrix metalloproteins, which are chemoattractants for inflammatory cells (13,14). Cyclophilin A therefore plays a key mediator role in affecting endothelial cell, vascular smooth muscle cell, and inflammatory cell functions in oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Value of Cyclophilin A in Acute Ischemic Stroke

Karaca¹,

Tatlı²,

Eryiğit³

et al. 2017

EAJEM

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Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages

Cited by 124 publications

References 26 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

Diagnostic Value of Cyclophilin A in Acute Ischemic Stroke

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