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Tumor necrosis factor alpha-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis.

ABSTRACT: INTRODUCTION: Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNFalpha antagonists in RA is poorly defined. Immunization of DBA/1 mice with glucose-6-phosphate isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFalpha antagonists, suggesting similar etiology to RA. In this study, we explored TNFalpha-related mechanisms of arthritis. METHODS: First, we performed GeneChip analysis using splenocytes of mice with GPI-induced arthritis. Expression of TNFalpha-induced adipose-related protein (TIARP) mRNA and protein in spleens, joints and lymph nodes was evaluated, and fluctuation of TIARP mRNA was analyzed after administration of anti-TNFalpha monoclonal antibody (mAb). Localization of TIARP in spleen and joints was also explored. Six-transmembrane epithelial antigen of the prostate (STEAP) families of proteins, the human ortholog of TIARP gene, were also evaluated in human peripheral blood mononucleocytes and synovium. RESULTS: Among the arrayed TNFalpha-related genes, the expression of TIARP mRNA was the highest (more than 20 times the control). TIARP mRNA was detected specifically in joints and spleens of arthritic mice, and their levels in the synovia correlated with severity of joint swelling. Treatment with anti-TNF mAb significantly reduced TIARP mRNA expression in splenocytes. Among the splenocytes, CD11b+ cells were the main source of TIARP mRNA. Immunohistochemistry showed that TIARP protein was mainly localized in hyperplastic synovium. Among the STEAP family of proteins, STEAP4 was highly upregulated in joints of patients with RA and especially co-localized with CD68+ macrophages. CONCLUSIONS: The results shed light on the new mechanism of action of TNFalpha antagonists in autoimmune arthritis, suggesting that TIARP plays an important role in inflammatory arthritis, through the regulation of inflammatory cytokines.

SUBMITTER: Inoue A

PROVIDER: S-EPMC2745801 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Tumor necrosis factor alpha-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis.

Inoue Asuka A Matsumoto Isao I Tanaka Yoko Y Iwanami Keiichi K Kanamori Akihiro A Ochiai Naoyuki N Goto Daisuke D Ito Satoshi S Sumida Takayuki T

Arthritis research & therapy 20090806 4

<h4>Introduction</h4>Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNFalpha antagonists in RA is poorly defined. Immunization of DBA/1 mice with glucose-6-phosphate isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFalpha antagonists, suggesting similar etiology to RA. In this study, we explored TNFalpha-related mechanisms of arthritis.<h4>Methods</h4>First, we performed GeneChip a ...[more]

PMID: 19660107

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Project description:Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (white peony, WP) in treating immune inflammatory diseases of rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis) by using network pharmacology and molecular docking. Methods: In this study, the ingredient of WP and the potential inflammatory targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard, and OMIM databases, respectively. The establishment of the RA-WP-potential inflammatory target gene interaction network was accomplished using the STRING database. Network maps of the WP-RA-potential inflammatory target gene network were constructed using Cytoscape software. Gene ontology (GO) and the biological pathway (KEGG) enrichment analyses were used to further explore the RA mechanism and therapeutic effects of WP. Molecular docking technology was used to analyze the optimal effective components from WP for docking with TNF-α. Results: Thirteen active ingredients and 71 target genes were screened from WP, and 49 of the target genes intersected with RA target inflammatory genes and were considered potential therapeutic targets. Network pharmacological analysis showed that the WP active ingredients such as mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA inflammatory target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, and CHRM2, respectively. The immune-inflammatory signaling pathways of the active ingredients for the treatment of RA are the TNF-α signaling pathway, Toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated protein kinase, etc. Molecular docking results suggested that mairin was the most appropriate natural TNFis. Conclusion: Our findings provide an essential role and basis for further immune-inflammatory studies into the molecular mechanisms of WP and TNFis development in RA.

Project description:ObjectiveWe have previously reported that stimulation of mouse bone marrow-derived macrophages with tumor necrosis factor (TNF) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells. We undertook this study to clarify the characterization and function of human TNF and IL-6-induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors.MethodsPeripheral blood monocytes were cultured with a combination of TNF and IL-6, TNF alone, IL-6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL-6-induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole-body bone mineral density (BMD) was examined.ResultsPeripheral blood monocytes stimulated with a TNF and IL-6-induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL-6-induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL-6-induced osteoclasts, but not in RANKL-induced osteoclasts. The number of TNF and IL-6-induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients.ConclusionOur results demonstrate that TNF and IL-6-induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.

Project description:OBJECTIVE:Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. METHODS:A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (triangle upDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. RESULTS:Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the triangle upDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99). CONCLUSION:Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.

Dataset Information

Tumor necrosis factor alpha-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis.

Publications

Tumor necrosis factor alpha-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis.

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