Overexpression of CXC chemokine ligand 14 exacerbates collagen-induced arthritis.

Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
The Journal of Immunology (Impact Factor: 5.36). 03/2010; 184(8):4455-9. DOI: 10.4049/jimmunol.0900525
Source: PubMed

ABSTRACT CXCL14 is a relatively new chemokine with unidentified receptor and undefined function. Recently, we found that CXCL14 is upregulated in arthritic joints in a mouse model of autoimmune arthritis, collagen-induced arthritis. To examine the role of CXCL14 in the development and pathogenesis of autoimmune arthritis, we have generated transgenic (Tg) mice that overexpress CXCL14 under control of phosphoglycerate kinase promoter. The results showed that CXCL14-Tg mice developed more severe arthritis compared with wild-type controls. The draining lymph nodes of CXCL14-Tg mice were significantly enlarged and contained an increased number of activated T cells, particularly the CD44(+)CD62L(low) effector memory cells. In addition, T cells from CXCL14-Tg mice exhibited an enhanced proliferative response against collagen II and produced higher levels of IFN-gamma but not IL-4 or IL-17. CXCL14-Tg mice also had elevated levels of IgG2a autoantibodies. These findings indicated that CXCL14 plays an important role in the autoimmune arthritis, which may have an implication in understanding the pathogenic mechanisms of rheumatoid arthritis in humans and, ultimately, therapeutic interference.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia stimulates synovial hypoperfusion in rheumatoid arthritis (RA). TXNDC5 stimulates cellular proliferation in hypoxic conditions. We previously detected increased TXNDC5 expression in synovial tissues and blood from RA patients and demonstrated that the gene encoding TXNDC5 increased RA risk. The present study investigated the pathogenic roles of TXNDC5 in RA. Transgenic mice that over-expressed TXNDC5 (TXNDC5-Tg) were generated using C57BL/6J mice and treated with bovine collagen II to induce arthritis (CIA). Synovial fibroblasts from RA patients (RASFs) were cultured and incubated with TXNDC5-siRNA or CoCl(2), a chemical that induces hypoxia. CIA was observed in 80% of the TXNDC5-Tg, but only 20% of the wild-type mice (WT) developed CIA. The clinical arthritis scores reached 5 in the TXNDC5-Tg, but this index only reached 2 in the control mice. CIA TXNDC5-Tg exhibited clear pannus proliferation and bone erosion in joint tissues. A significant increase in CD4 T cells was observed in the thymus and spleen of TXNDC5-Tg during CIA. Serum levels of anti-collagen II IgG, IgG1 and IgG2a antibodies were significantly elevated in the mice. Increased cell proliferation, cell migration and TXNDC5 expression were observed in RASFs following incubation with 1 µM CoCl(2). However, this effect was diminished when TXNDC5 expression was inhibited with 100 nM siRNA. TNF-alpha, IL-1α, IL-1β and IL-17 levels were significantly increased in the blood of TXNDC5-Tg mice, but the levels of these cytokines declined in the supernatant of RASFs that were treated with TXNDC5 siRNA. The expression of adiponectin, a cytokine-like mediator, decreased significantly in RASFs following TXNDC5 siRNA treatment. These results suggest that TXNDC5-over-expressing mice were susceptible to CIA. This study also suggests that hypoxia induced TXCNDC5 expression, which contributed to adiponectin expression, cytokine production and the cellular proliferation and migration of fibroblasts in RA.
    PLoS ONE 01/2013; 8(1):e53301. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES: Soluble C-X-C chemokine ligand 16 (CXCL16) was shown to recruit polymorphonuclear cells into synovial tissue in gout patients. The aim of this study was to explore the pathophysiological characteristics of CXCL16 in gout patients with or without chronic kidney disease (CKD). DESIGN AND METHODS: 42 gout patients, 22 CKD and 20 healthy subjects were enrolled. Plasma CXCL16 and other biochemical parameters were tested. RESULTS: Plasma CXCL16 levels in gout subjects with CKD were significantly increased compared with healthy, CKD and gout subjects without CKD. Soluble CXCL16 levels in gout subjects were closely correlated with renal function and lipid profiles, and independently associated with 24h proteinuria, creatinine clearance rate and C-reactive protein. CONCLUSION: Our data indicated that plasma CXCL16 levels are significantly increased in gout patients with and without CKD, and are independently associated with renal function. Elucidating the pathophysiologcial role of CXCL16 in gout patients requires further study.
    Clinical biochemistry 05/2012; · 2.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: A low pH microenvironment is a characteristic feature of inflammation loci and affects the functions of immune cells. In this study, we investigated the effect of extracellular acidification on macrophage gene expression. METHODS: RAW264.7 macrophages were incubated in neutral (pH 7.4) or acidic (pH 6.8) medium for 4 h. Global mRNA expression levels were determined using Affymetrix genechips. RESULTS: The mRNA expressions of 353 macrophage genes were significantly modified after incubation in acidic medium; 193 were up-regulated and 160 down-regulated. Differentially regulated genes were grouped into 13 classes based on the functions of the corresponding protein products. Pathway analysis revealed that differentially expressed genes are enriched in pathways related to inflammation and immune responses. Quantitative real-time PCR analysis confirmed that the expressions of CXCL10, CXCL14, IL-18, IL-4RA, ABCA1, CCL4, IL-7R, CXCR4, TLR7, and CCL3 mRNAs were regulated by extracellular acidification. CONCLUSION: The results of this study provide insights into the effects of acidic extracellular environments on macrophage gene expression.
    Agents and Actions 02/2013; · 2.14 Impact Factor


Available from