STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

Kuuliala, Krista; Kuuliala, Antti; Koivuniemi, Riitta; Kautiainen, Hannu; Repo, Heikki; Leirisalo‐Repo, Marjatta

doi:10.1371/journal.pone.0167975

Cited by 16 publications

(14 citation statements)

References 49 publications

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“…These genes are significantly up-regulated in the development of RA, and moreover, the expression levels of 10 genes (OAS1, STAT1, IFIT3, IFIT2, IFI6, RSAD2, OASL, GBP2, IRF7 and IFIT1) are also negatively associated with the therapeutic response of infliximab in RA patients. Most of these genes (nine out of tengenes) have been reported to be involved in the occurrence, development and therapeutic response of RA(30)(31)(32)(33)(34), and physio pathological processes of the immune system(35), confirming the results of bioinformatics mining based on the RA dataset from the GEO database are highly credible and accurate. However, the correlation of the one remaining genes (GBP2), which have the third most significant differential expression between the infliximab-responsive samples and infliximabunresponsive sampleswith RA, has not been confirmed by basic and clinical studies and attracted us…”

supporting

confidence: 57%

Mining biomarkers for the occurrence, development and therapeutic response to infliximab of rheumatoid arthritis based on weighted gene co-expression network analysis

Wang

Zhang

Chen

et al. 2020

Preprint

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Rheumatoid arthritis (RA) is a chronic systemic autoimmune and recurrent disease characterized by joint lesion with high disability rate and poor prognosis. Although anti-TNF therapy (infliximab) has been validated to be effective in controlling the symptoms of RA, more than one-third of patients cannot benefit from anti-TNF therapy. Therefore, it is critical to explore novel biomarkers associated with the occurrence and development of the disease, and therapeutic response of infliximab treatment. In this study, we first analyzed differentially expressed genes (DEGs) between RA patients and healthy controls. Subsequently, WGCNA was used to analyze the co-expression module (tan module) associated with the therapeutic response of infliximab treatment in RA, which further found that the genes (a total of 102) in the module tan were also the DEGs between RA patients and healthy controls (confirming that the close correlation of these genes with the occurrence and development of RA). Subsequently, enrichment analysis revealed that these 102 genes were mainly related to the body’s inflammatory immune response and the functions of NOD-like receptor signaling pathway as well as miR-146a-5p. Moreover, protein-protein interaction (PPI) was constructed on the 102 genes, followed by mining the key genes in the network (a total of 14 genes) by topological analysis. Finally, we confirmed that 10 genes (OAS1, STAT1, IFIT3, IFIT2, IFI6, RSAD2, OASL, GBP2, IRF7 and IFIT1) were potential biomarkers for the occurrence and development, as well as the therapeutic response against infliximab treatment in RA by analyzing the differences in the expressions of these genes between RA and healthy control samples, as well as drug response and non-response samples. Therefore, this study can provide guidance on medication selection and prognostic prediction of RA patients for clinicians, which can also identify relevant genes to provide therapeutic targets for precise medicine.

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supporting

confidence: 57%

Mining biomarkers for the occurrence, development and therapeutic response to infliximab of rheumatoid arthritis based on weighted gene co-expression network analysis

Wang

Zhang

Chen

et al. 2020

Preprint

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“…In addition, KC also inhibited the activation of STAT1 and STAT6, as phosphorylated forms of STAT1 and STAT6 were found to be decreased in the KC-treated RAW264.7 cells stimulated by LPS. STAT1 and STAT6 have been reported to be increasingly expressed in rheumatoid arthritis, wherein they mediate the secretion of inflammatory mediators [34,35]. It is also possible that the action of KC on STAT1 activation might be linked to the suppression of LPS-induced IFN-β, as IFN-β is a principle STAT1-activating cytokine [36].…”

Section: Discussionmentioning

confidence: 99%

In vitro Anti-Inflammatory and Anti-Oxidative Stress Activities of Kushenol C Isolated from the Roots of Sophora flavescens

Cho¹,

Nchang

Kim

et al. 2020

Molecules

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Kushenol C (KC) is a prenylated flavonoid isolated from the roots of Sophora flavescens aiton. Little is known about its anti-inflammatory and anti-oxidative stress activities. Here, we investigated the anti-inflammatory and anti-oxidative stress effects of KC in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, and tert-butyl hydroperoxide (tBHP)-induced oxidative stress in HaCaT cells. The results demonstrated that KC dose-dependently suppressed the production of inflammatory mediators, including NO, PGE2, IL-6, IL1β, MCP-1, and IFN-β in LPS-stimulated RAW264.7 macrophages. The study demonstrated that the inhibition of STAT1, STAT6, and NF-κB activations by KC might have been responsible for the inhibition of NO, PGE2, IL-6, IL1β, MCP-1, and IFN-β in the LPS-stimulated RAW264.7 macrophages. KC also upregulated the expression of HO-1 and its activities in the LPS-stimulated RAW264.7 macrophages. The upregulation of Nrf2 transcription activities by KC in the LPS-stimulated RAW264.7 macrophages was demonstrated to be responsible for the upregulation of HO-1 expression and its activity in LPS-stimulated RAW264.7 macrophages. In HaCaT cells, KC prevented DNA damage and cell death by upregulating the endogenous antioxidant defense system involving glutathione, superoxide dismutase, and catalase, which prevented reactive oxygen species production from tert-butyl hydroperoxide (tBHP)-induced oxidative stress in HaCaT cells. The upregulated activation of Nrf2 and Akt in the PI3K-Akt signaling pathway by KC was demonstrated to be responsible for the anti-oxidative stress activity of KC in HaCaT cells. Collectively, the study suggests that KC can be further investigated as a potential anti-inflammatory candidate for the treatment of inflammatory diseases.

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“…Whether pIRAK-4 may also serve as a marker for anakinra responsiveness in RA patients remains to be defined. Other phosphorylated signaling molecules, such as JAK2 and 3, STAT1, 3, and 6 in different leukocyte subsets, have been examined as markers of treatment response in smaller RA collectives by ( 20 – 22 ). However, trials to establish IRAK-4 inhibitors as a new therapy in rheumatoid arthritis are underway ( 23 ), which underlines the possible value of this target.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome

et al. 2020

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Schnitzler syndrome (SchS) is a rare autoinflammatory disease, characterized by urticarial rash, recurrent fever, osteo-articular pain/arthritis with bone condensation, and monoclonal gammopathy. Diagnosis may be difficult due to overlapping signs with other diseases. Here, we describe the case of a 62-year-old man with SchS, who was initially misdiagnosed with multicentric Castleman disease (MCD). As excessive release of IL-6 is characteristic of MCD, in contrast to IL-1 in SchS, we measured the phosphorylation of intracellular signaling proteins of the respective pathways by flow cytometry. We found a distinct increase of phosphorylated IRAK-4 in our patient’s B cells and monocytes while phosphorylation of STAT-3 was low, suggesting predominant IL-1 signaling. In accordance with these results and the classification criteria, we established the diagnosis of SchS instead of MCD and commenced therapy with the IL-1 receptor antagonist anakinra. We observed a rapid remission of signs accompanied by a reduction of phosphorylated IRAK-4 to normal levels. In conclusion, we propose phosphorylated IRAK-4 in B cells and monocytes as a potential marker for diagnosis of SchS and for treatment response to IL-1 blockade.

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STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

Cited by 16 publications

References 49 publications

Mining biomarkers for the occurrence, development and therapeutic response to infliximab of rheumatoid arthritis based on weighted gene co-expression network analysis

Mining biomarkers for the occurrence, development and therapeutic response to infliximab of rheumatoid arthritis based on weighted gene co-expression network analysis

In vitro Anti-Inflammatory and Anti-Oxidative Stress Activities of Kushenol C Isolated from the Roots of Sophora flavescens

Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome

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