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Investigation of gene expression profiles in a rat adjuvant arthritis model suggests an effective role of triptolide via PI3K-AKT signaling.

ABSTRACT: Rheumatoid arthritis (RA) is a common systemic autoimmune disease mainly involving the formation of a synovial pannus, for which no effective treatment is available. In order to study the molecular biological mechanisms underlying the inhibition of RA synovial pannus by triptolide, differentially expressed genes in synovial tissues from an adjuvant arthritis (AA) rat model with and without triptolide treatment were detected in an mRNA microarray profile produced by Agilent Technologies and verified by reverse transcription-quantitative polymerase chain reaction analysis (RT-qPCR). An AA model was established by subcutaneously injecting 0.1 ml Freund's complete adjuvant daily for 18 days and scored by arthritis index assessment. Subsequently, triptolide (0.4 mg/kg) or an equivalent amount of saline was administered daily for 14 days. At the end of the experiment, synovial tissues were obtained from the ankle joints of the rats' hind legs. Total RNA was extracted and purified, and microarray hybridization was used to obtain the gene expression profile for RA with and without triptolide treatment. A total of 48 genes were identified to be differentially expressed between the treatment and model groups, including 32 upregulated and 16 downregulated genes. The possible signaling pathways associated with the effect of triptolide were investigated by Gene Ontology and pathway analysis, revealing that the phosphoinositide-3 kinase (PI3K)/AKT signaling pathway has a key role in the proliferation and apoptosis of synovial cells in RA joints. Reverse transcription-quantitative polymerase chain reaction analysis was applied to confirm the aberrant expression of key mRNAs and revealed that vascular endothelial growth factor (VEGF) A and C1q and tumor necrosis factor related protein 3 (C1QTNF3) were downregulated in the treatment group compared with the model group (P<0.05). In conclusion, triptolide may exert its effects against RA via the PI3K/AKT pathway and has an inhibitory effect on the expression of VEGFA and C1QTNF3, thus are potentially associated with the occurrence and development of RA.

SUBMITTER: Zou Y

PROVIDER: S-EPMC6447910 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Investigation of gene expression profiles in a rat adjuvant arthritis model suggests an effective role of triptolide via PI3K-AKT signaling.

Zou Yang Y Hu Weifeng W

Experimental and therapeutic medicine 20190320 5

Rheumatoid arthritis (RA) is a common systemic autoimmune disease mainly involving the formation of a synovial pannus, for which no effective treatment is available. In order to study the molecular biological mechanisms underlying the inhibition of RA synovial pannus by triptolide, differentially expressed genes in synovial tissues from an adjuvant arthritis (AA) rat model with and without triptolide treatment were detected in an mRNA microarray profile produced by Agilent Technologies and verif ...[more]

PMID: 30988781

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Project description:ObjectiveCC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1alpha (MIP-1alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat.MethodsUsing immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA.ResultsAdministration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1alpha and MIP-1beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor alpha, interleukin-1beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint.ConclusionThe data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.

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Investigation of gene expression profiles in a rat adjuvant arthritis model suggests an effective role of triptolide via PI3K-AKT signaling.

Publications

Investigation of gene expression profiles in a rat adjuvant arthritis model suggests an effective role of triptolide via PI3K-AKT signaling.

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