Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling

Abstract

Transcriptional regulation of inducible nitric oxide synthase (iNOS) is critically involved in the pathogenesis and progression of rheumatoid arthritis (RA); however, the specific transcription factors that control this process remain largely unidentified. In the present study, it was discovered that expression of the key erythroid factor, globin transcription factor 1 (GATA1), is significantly greater in human RA synovial tissues than in osteoarthritis (OA) tissues. IL 6 was found to induce synovial GATA1 expression in a signal transducer and activator of transcription 3-dependent manner. Functionally, knockdown of GATA1 expression using specific small interfering RNA treatment was found to compromise immunoreaction-elicited expression of proinflammatory cytokines and thus impair invasiveness of the human fibroblast-like synovial cell line MH7A, whereas introduction of exogenous GATA1 was found to promote production of proinflammatory cytokines, leading to greater aggressiveness of MH7A cells. Mechanistically, GATA1 acts as the transcriptional coactivator of NOS2 (the gene encoding iNOS) transcription. Collectively, these data suggest that synovial GATA1 is an essential contributor to development and exacerbation of RA, presumably by inducing NOS2 transcription.

Deciphering the Pharmacological Mechanisms of the Huayu-Qiangshen-Tongbi Formula Through Integrating Network Pharmacology and In Vitro Pharmacological Investigation

“…As shown in Figure 4 , the HT extract significantly reduced the secretion of IL-6 and NO under the nontoxic dosages, which indicated that the HT formula would be a potential anti-inflammatory formula in accordance with the prediction results. Furthermore, our experimental results suggested that the HT extract could decrease the LPS-induced excessive expression of the iNOS ( Figure 5 ), which has been reported to promote the production of IL-6 and NO during the development of RA (Li et al, 2017; Liu et al, 2018). As well known, iNOS is the downstream signal in the network of inflammatory cascade reaction, and several signaling pathways including the Toll-like receptor signaling pathway (Li et al, 2019), PI3K–Akt signaling pathway (Cao et al, 2019), HIF-1 signaling pathway (Lee et al, 2018), and TNF signaling pathway (Pooladanda et al, 2019) from our prediction results have been reported to regulate inflammation by mediating the expression of iNOS.…”

Protective Role of Optineurin Against Joint Destruction in Rheumatoid Arthritis Synovial Fibroblasts

“…A recent study characterized the inflammatory role of GATA1 in RASFs , and therefore we evaluated the expression of GATA1 in OPTN–down‐regulated RASFs. Overall, the expression of GATA1 was obviously higher after down‐regulating OPTN, but the difference compared to control RASFs was not significant (Figure F) due to the wide range of standard deviation among patients.…”

Recovery of synaptic loss and depressive-like behavior induced by GATA1 through blocking of the neuroinflammatory response

“…We speculate that an increase in anti-inflammatory cytokines may have resulted from an immunomodulatory response to neuroinflammation. Although not in the CNS, there were several reports that GATA1 was involved in the expression of inflammatory mediators in the peripheral system ( Masuda et al, 2004 ; Nigo et al, 2006 ; El Gazzar, 2007 ; Cole et al, 2010 ; Liu et al, 2018 ; Abdul Qayum et al, 2019 ). These findings might support the notion that GATA1 is involved in the inflammatory process.…”