The arthritis severity locus Cia5a regulates the expression of inflammatory mediators including Syk pathway genes and proteases in pristane-induced arthritis

Abstract

BackgroundCia5a is a locus on rat chromosome 10 that regulates disease severity and joint damage in two models of rheumatoid arthritis, collagen- and pristane-induced arthritis (PIA). In this study, we aimed to identify cellular and molecular processes regulated by Cia5a using microarray-based gene expression analysis of synovial tissues from MHC identical DA (severe erosive disease) and DA.F344(Cia5a) congenics (mild non-erosive disease) rats.ResultsSynovial tissues from six DA and eight DA.F344(Cia5a) rats were analyzed 21 days after the induction of PIA using the Illumina RatRef-12 BeadChip (21,922 genes) and selected data confirmed with qPCR. There was a significantly increased expression of pro-inflammatory mediators such as Il1b (5-fold), Il18 (3.9-fold), Cxcl1 (10-fold), Cxcl13 (7.5-fold) and Ccl7 (7.9-fold), and proteases like Mmp3 (23-fold), Mmp9 (32-fold), Mmp14 (4.4-fold) and cathepsins in synovial tissues from DA, with reciprocally reduced levels in congenics. mRNA levels of 47 members of the Spleen Tyrosine Kinase (Syk) pathway were significantly increased in DA synovial tissues compared with DA.F344(Cia5a), and included Syk (5.4-fold), Syk-activating receptors and interacting proteins, and genes regulated by Syk such as NFkB, and NAPDH oxidase complex genes. Nuclear receptors (NR) such as Rxrg, Pparg and Rev-erba were increased in the protected congenics, and so was the anti-inflammatory NR-target gene Scd1 (54-fold increase). Tnn (72-fold decrease) was the gene most significantly increased in DA.ConclusionsAnalyses of gene expression in synovial tissues revealed that the arthritis severity locus Cia5a regulates the expression of key mediators of inflammation and joint damage, as well as the expression of members of the Syk pathway. This expression pattern correlates with disease severity and joint damage and along with the gene accounting for Cia5a could become a useful biomarker to identify patients at increased risk for severe and erosive disease. The identification of the gene accounting for Cia5a has the potential to generate a new and important target for therapy and prognosis.

The Dietary Flavonoid Kaempferol Mediates Anti‐Inflammatory Responses via the Src, Syk, IRAK1, and IRAK4 Molecular Targets

“…Thus, tissue and cellular damage that occurs under both infected and sterile conditions can induce the activation of NF- κ B and AP-1 via pattern recognition receptors such as TLRs in a similar manner [ 58 ]. Previous reports [ 60 – 62 ] and our data strongly indicate that the activation of Src, Syk, IRAK1, and IRAK4 is present in both in vitro and in vivo inflammatory models (Figures 3 and 4 , data not shown). In addition, KF strongly inhibits the phosphorylation and subsequent enzyme activity of Src, Syk, IRAK1, and IRAK4, which is linked to its anti-inflammatory action (Figures 3 and 4 ).…”

Proprotein convertase subtilisin/kexin type 6 promotes in vitro proliferation, migration and inflammatory cytokine secretion of synovial fibroblast-like cells from rheumatoid arthritis via nuclear-κB, signal transducer and activator of transcription 3 and extracellular signal regulated 1/2 pathways

“…Xue et al (24) reported that endogenous MMP-9 contributes to prolonged survival and invasive and inflammatory properties of RASFs. While MMP-9 is able to degrade the extracellular matrix, it is also implicated in the development of cartilage and bone erosion in RA (25). A previous study by Perisic et al (26) demonstrated that PCSK6 mRNA expression levels are positively correlated with typical markers of inflammation and apoptosis, including IL-1β and TNF-α, and proteins involved in matrix degradation, such as MMP-9, in vascular disease.…”

A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation

“…We observed similar results with R406 in the human RA-derived synoviocyte cell line MH7A (see text). Moreover, Syk pathway genes are upregulated in synovial tissues from CIA-susceptible rodents when compared to CIA-resistant congenic controls [ 47 ]. In the context of lupus, T-cells from a subset of patients display aberrant signaling due to abnormal recruitment of Syk to the T-cell receptor (TCR) complex.…”