Soluble CD14 Induces Pro-inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-Like Synovial Cells via Toll-Like Receptor 4

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-a, 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.

The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis

“…Along the same line, sCD14 levels are increased in RA synovial fluid and serum compared with osteoarthritis patients (59,60). sCD14 plays an important role in mediating the immune responses to LPS of CD14-negative cells such as endothelial cells and epithelial cells and induces proinflammatory cytokines in fibroblast-like synovial cells from RA patients (61). The modulation of CD14 expression by antifolates that we now report supports the anti-inflammatory role of MTX in RA patients and leads us to suggest that MTX-treated RA patients would exhibit lower levels of sCD14 and mCD14 in myeloid cells, lower responsiveness to TLR4-dependent damageassociated molecular patterns (DAMPs), and a lower proinflammatory profile.…”

The macrophage reprogramming ability of antifolates reveals soluble CD14 as a potential biomarker for methotrexate response in rheumatoid arthritis

“…Along the same line, sCD14 levels are increased in RA synovial fluid and serum compared to osteoarthritis patients (55,56). sCD14 plays an important role in mediating the immune responses to LPS of CD14-negative cells such as endothelial cells and epithelial cells, and induces proinflammatory cytokines in fibroblast-like synovial cells from RA patients (57). The modulation of CD14 expression by antifolates that we now report supports the anti-inflammatory role of MTX in RA patients and leads us to suggest that MTX-treated RA patients would exhibit lower levels of sCD14 and mCD14 in myeloid cells, lower responsiveness to TLR4-dependent DAMPs, and a lower proinflammatory profile.…”

The Alterations in CD14 Expression in Periodontitis: A Systematic Review

“…Hence further solidifying its role periodontal disease. Recently the role of sCD14 transducing and activating passage ways that could influence osteoclast genesis have been proposed [58].…”