Abstract
Objectives: Synovial fluids of rheumatoid arthritis (RA) patients commonly contain high concentrations of soluble CD14 (sCD14). To investigate its potential role in RA pathogenesis, we tested whether sCD14 binding transmits a signal to fibroblast-like synoviocytes from RA patients (RA-FLS). Methods: The induction of pro-inflammatory cytokines, chemokines, and mediators by sCD14 stimulation of RA-FLS was quantified by real-time PCR and ELISA. Cell proliferation was assessed by the BrdU assay. LPS-RS, a Toll-like receptor 4 (TLR-4) antagonist, was used to block TLR-4 signaling. Results: Soluble CD14 induced the expression of IL-6 mRNA and secretion of the protein. The expression of other pro-inflammatory cytokines and mediators, such as TNF-α, IL-8, intercellular adhesion molecule-1 (ICAM-1), MMP-3, and RANK ligand (RANKL), was also induced by sCD14. In addition, sCD14 stimulation promoted RA-FLS proliferation. LPS-RS abolished IL-6, IL-8, and ICAM-1 mRNA induction by sCD14 in RA-FLS. On the other hand, TNF-α and IL-17A increased TLR-4 expression by RA-FLS and amplified their sCD14-induced IL-6 expression. Conclusions: Soluble CD14 transmits inflammatory signals to RA-FLS via TLR-4. The effects of sCD14 may be augmented in inflammatory milieu. Our results suggest that sCD14 is involved in the pathogenesis of RA and may be a novel therapeutic target.
Highlights
rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and hyperplastic synovial tissue, which subsequently cause cartilage and bone destruction [1]
We found that IL-6 mRNA expression was induced by soluble CD14 (sCD14) at a concentration of 500 ng/mL (Figure 1A) and reached a maximum after 3 h (Figure 1B)
These results suggest that sCD14 facilitates synthesis of IL-6 by RA-Fibroblast-like synoviocytes (FLS)
Summary
RA is characterized by chronic synovial inflammation and hyperplastic synovial tissue, which subsequently cause cartilage and bone destruction [1]. “imprinted aggressors”, i.e., the presence of activated FLS reflects a proinflammatory milieu, but on the other hand, they act as primary promoters of inflammation, persistently synthesizing cytokines, chemokines, MMP, and adhesion molecules. This dual behavior suggests that FLS-directed therapies could become a complementary approach to the use of biological compounds that suppress the synthesis of key inflammatory cytokines such as TNF-α [2,3]. LPS bound to CD14 is transferred to the Toll-like receptor-4 (TLR-4)-myeloid differentiation factor 2 (MD-2) complex, where it subsequently delivers intracellular signals [4,5,6]
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