CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes

Migita, Kiyoshi; Komori, Atsumasa; Torigoshi, Takafumi; Maeda, Yümi; Izumi, Yuichi; Jiuchi, Yuka; Miyashita, Taiichiro; Nakamura, Minoru; Motokawa, Satoru; Ishibashi, Hiromi

doi:10.1186/ar3333

Cited by 45 publications

(40 citation statements)

References 29 publications

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“…Although these two receptors have many overlapping biological responses, they still have some different functions through various signal pathways in specific cell types (Gomez‐Lechoz, 1999). When OSM binds to gp130 subunit, it triggers heterodimerization of the receptors and activates Jannus Kinase (JAK) family (Migita et al, 2011). Activation of JAKs results in phosphorylation of the cytoplasmic tail of the receptors and creates a docking site for signal transducer and activator of transcription family (STATs), which is further phosphorylated and transported into nucleus.…”

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confidence: 99%

Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma

et al. 2011

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We read with interest the reviews by Ghouri et al. 1 and Martinez et al. 2 Ghouri et al. analyzed the association of nonalcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) and concluded that although a diagnosis of NAFLD should prompt diabetes screening, it is insufficient for considering patients to be at high risk for CVD. Martinez et al. evaluated noninvasive methods for assessing liver fibrosis and recommended that those tests with the highest diagnostic accuracy be validated against liver biopsy to facilitate their implementation in clinical practice.We meta-analyzed prospective data regarding the natural history of NAFLD and studies assessing the diagnostic accuracy of noninvasive methods for liver disease severity against liver biopsy in NAFLD, and we reached the following conclusions 3 :1. The two NAFLD histological subtypes, simple steatosis (SS) and nonalcoholic steatohepatitis (NASH), have different risks of liver-related complications: SS progresses to cirrhosis in less than 5% of cases; NASH progresses to cirrhosis in 10% to 15% of cases over 10 years and in 25% to 30% of cases in the presence of advanced fibrosis. 2. NAFLD patients have a 1.44-to 2.05-fold higher rate of CVD (depending on whether the diagnosis is based on an aminotransferase elevation or radiological/histological criteria) than the general population; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Importantly, CVD mortality did not differ among NAFLD histological subtypes. ; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Whether the risk of diabetes differs among NAFLD histological subtypes remains unclear: in a communitybased study, the 13-year incidence of diabetes was 2.98-fold higher in NASH patients versus SS patients. 3According to our analysis, a diagnosis of NAFLD should prompt a thorough three-focus assessment of cardiovascular, metabolic, and liver-related risks (Table 1). 4 Liver-related risk assessment remains problematic because it requires liver histology. Three noninvasive methods have been extensively validated: enzyme-linked immunosorbent assay-detected cytokeratin 18 fragments (9 studies enrolling 856 participants) for the detection of NASH and the NAFLD fibrosis score (13 studies enrolling 3064 participants) and FibroScan (6 studies enrolling 563 participants) for the detection of advanced fibrosis. We believe that these methods should be promptly implemented in diagnostic algorithms to select patients for liver biopsy in routine clinical practice while we continue to search for the ideal noninvasive marker.

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confidence: 99%

Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma

et al. 2011

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“…JAK2 inhibitors are classic therapeutics for myeloproliferative diseases because mutations of JAK2, which is associated with erythropoietin and tyrosine stromal lymphopoietin receptors, play a critical role (19)(20)(21). Recently, the JAK2 inhibitors CEP-33779 and SB1578 were investigated in an RA model (22,23). AG490 has been widely used as a JAK2 inhibitor in various settings, and it appears to specifically suppress JAK2/STAT3 signaling (24)(25)(26)(27).…”

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confidence: 99%

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

Park

Lee

Lim

et al. 2014

The Journal of Immunology

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IL-6–mediated STAT3 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis. To investigate the molecular mechanism underlying the antirheumatic effects and T cell regulatory effects of STAT3 inhibition, we studied the effects of the JAK 2 inhibitor AG490 on Th17 cell/regulatory T cell (Treg) balance and osteoclastogenesis. AG490 was administered to mice with collagen-induced arthritis (CIA) via i.p. injection, and its in vivo effects were determined. Differential expression of proinflammatory cytokines, including IL-17A, IL-1β, and IL-6, was analyzed by immunohistochemistry. Levels of phosphorylated STAT3 and STAT5 and differentiation of Th17 cells and Tregs after AG490 treatment in our CIA model were analyzed by immunostaining. In vitro development of Th17 cells and Tregs was analyzed by flow cytometry and real-time PCR. AG490 ameliorated the arthritic phenotype in CIA and increased the proportion of Foxp3+ Tregs. In contrast, the proportion of IL-17A–producing T cells and levels of inflammatory markers were reduced in AG490-treated mice. Numbers of p-STAT3+ CD4+ T cells and p-STAT5+ CD4+ T cells were reduced and elevated, respectively, after treatment with AG490. Furthermore, AG490 markedly increased the expression of molecules associated with Treg development (ICOS, programmed cell death protein 1, ICAM-1, and CD103). The development and function of osteoclasts were suppressed by AG490 treatment. Our results suggest that AG490, specifically regulating the JAK2/STAT3 pathway, may be a promising treatment for rheumatoid arthritis.

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“…Among those pathways, the functional relation of Jak-STAT signaling pathway with RA pathogenesis is shown in the reviews by Raychaudhuri [32] and Plenge [33]. The dramatic effects of JAK inhibitors on RA in clinical trials are recently discussed in [34].…”

Section: Resultsmentioning

confidence: 99%

A genetic algorithm approach to active subnetwork search applied to GWAS data

Özışık

Bakir-Gungor

Di̇ri̇

et al. 2013

2013 8th International Symposium on Health Informatics and Bioinformatics

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An active subnetwork is a group of interconnected genes that show condition-specific differences. It has been observed that the gene products that have alterations associated with a disease of interest, incline to be part of the subnetworks among the overall interaction network. Hence, the integration of the interaction data with the genotypic data underlying disease states facilitates the separation of the subnetworks perturbed in a given disorder from the rest of the network. In the literature, active subnetwork search is used to discover disease related regulatory pathways, dysregulated genes, functional modules, cancer markers, to classify diseases, and to predict response to treatment. In this study, a genetic algorithm based method is developed for active subnetwork search and applied to WTCCC Rheumatoid Arthritis genome-wide association study dataset. The relevance of the identified subnetworks against the disease is compared in terms of biological pathways. Our results show that the proposed method works well in detecting the significant RA associated subnetworks, and it is also applicable to recognize subnetworks of other complex diseases.

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CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes

Cited by 45 publications

References 29 publications

Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma

Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

A genetic algorithm approach to active subnetwork search applied to GWAS data

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