Dataset Information

The CO donor CORM-2 inhibits LPS-induced vascular cell adhesion molecule-1 expression and leukocyte adhesion in human rheumatoid synovial fibroblasts.

ABSTRACT:

Background and purpose

Infection with Gram-negative bacteria has been recognized as an initiator of rheumatoid arthritis, which is characterized by chronic inflammation and infiltration of immune cells. Carbon monoxide (CO) exhibits anti-inflammatory properties. Here we have investigated the detailed mechanisms of vascular cell adhesion molecule-1 (VCAM-1) expression induced by LPS and if CO inhibited LPS-induced leukocyte adhesion to synovial fibroblasts by suppressing VCAM-1 expression.

Experimental approach

Human rheumatoid arthritis synovial fibroblasts (RASFs) were incubated with LPS and/or the CO-releasing compound CORM-2. Effects of LPS on VCAM-1 levels were determined by analysing mRNA expression, promoter activity, protein expression, and immunohistochemical staining. The molecular mechanisms were investigated by determining the expression, activation, and binding activity of transcriptional factors using target signal antagonists.

Key results

CORM-2 significantly inhibited inflammatory responses in LPS-treated RASFs by down-regulating the expression of adhesion molecule VCAM-1 and leukocyte infiltration. The down-regulation of LPS-induced VCAM-1 expression involved inhibition of the expression of phosphorylated-NF-?B p65 and AP-1 (p-c-Jun, c-Jun and c-Fos mRNA levels). These results were confirmed by chromatin immunoprecipitation assay to detect NF-?B and AP-1 DNA binding activity.

Conclusions and implications

LPS-mediated formation of the TLR4/MyD88/TRAF6/c-Src complex regulated NF-?B and MAPKs/AP-1 activation leading to VCAM-1 expression and leukocyte adhesion. CORM-2, which liberates CO to elicit direct biological activities, attenuated LPS-induced VCAM-1 expression by interfering with NF-?B and AP-1 activation, and significantly reduced LPS-induced immune cell infiltration of the synovium.

SUBMITTER: Chi PL

PROVIDER: S-EPMC4055201 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

The CO donor CORM-2 inhibits LPS-induced vascular cell adhesion molecule-1 expression and leukocyte adhesion in human rheumatoid synovial fibroblasts.

Chi Pei-Ling PL Chuang Yu-Chen YC Chen Yu-Wen YW Lin Chih-Chung CC Hsiao Li-Der LD Yang Chuen-Mao CM

British journal of pharmacology 20140601 12

<h4>Background and purpose</h4>Infection with Gram-negative bacteria has been recognized as an initiator of rheumatoid arthritis, which is characterized by chronic inflammation and infiltration of immune cells. Carbon monoxide (CO) exhibits anti-inflammatory properties. Here we have investigated the detailed mechanisms of vascular cell adhesion molecule-1 (VCAM-1) expression induced by LPS and if CO inhibited LPS-induced leukocyte adhesion to synovial fibroblasts by suppressing VCAM-1 expression ...[more]

PMID: 24628691

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Project description:BackgroundAntcin K, an extract of Antrodia cinnamomea (a medicinal mushroom endemic to Taiwan commonly used in Chinese medicine preparations), inhibits proinflammatory cytokine production and angiogenesis in human rheumatoid arthritis synovial fibroblasts (RASFs), major players in RA disease. Antcin K also inhibits disease activity in mice with collagen-induced arthritis (CIA). Up until now, the effects of Antcin K upon cell adhesion molecules (CAMs) were unknown.MethodsRA and healthy synovial tissue samples (n = 10 in each group) were retrieved from the Gene Expression Omnibus (GEO) database (accession code: GDS5401) to compare CAM and monocyte marker expressions. In addition, synovial tissue samples from six RA patients and six patients undergoing arthroscopy for trauma/joint derangement (healthy controls) were subjected to immunohistochemical (IHC) analysis. mRNA and protein expression levels were analyzed in RASFs using RT-qPCR (Reverse transcription-quantitative polymerase chain reaction) and Western blot. RASFs were incubated with Antcin K and examined for monocyte adherence by fluorescence microscopy. Ankle joint tissue specimens from a CIA mouse model and healthy controls were stained with hematoxylin and eosin (H&E) and Safranin-O/Fast Green to examine histological changes and evidence of bone loss. IHC analysis determined levels of vascular cell adhesion molecule 1 (VCAM-1) and CD11b in CIA ankle tissue and clinical synovial tissue.ResultsLevels of VCAM-1 expression were higher in the GEO database specimens and the study's clinical samples of RA synovial tissue compared with the healthy specimens. Antcin K dose-dependently inhibited VCAM-1 expression and monocyte adhesion in RASFs. Antcin K also significantly inhibited levels of VCAM-1 and monocyte CD11b expression in CIA tissue. These effects appeared to be mediated by MEK1/2-ERK, p38, and AP-1 signaling.ConclusionsAntcin K seems promising for the treatment of RA and deserves further investigations.

Dataset Information

The CO donor CORM-2 inhibits LPS-induced vascular cell adhesion molecule-1 expression and leukocyte adhesion in human rheumatoid synovial fibroblasts.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

The CO donor CORM-2 inhibits LPS-induced vascular cell adhesion molecule-1 expression and leukocyte adhesion in human rheumatoid synovial fibroblasts.

Similar Datasets

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