Objective: To evaluate the anti-inflammatory mechanism of action of Chondroitin Sulphate (CS).
Design: THP-1 macrophages were cultured with a range of sizes and concentrations of HA fragments with TLR4 (LPS in a physiologically relevant concentration determined by analyses of sera of a community clinic ascertained knee osteoarthritis (OA) cohort) or TLR2 (heat killed listeria bacteria) agonists and varying concentrations of CS in a physiologically relevant range (10-200 mu g/ml). We measured IL-1 beta release, intracellular IL-1 beta ,proIL-1 beta, caspase-1 and NF-kappa B activity and DNA binding activity of NF-kappa B transcription factors from nuclear and cytoplasmic extracts.
Results: Serum LPS was significantly associated with radiographic knee joint space narrowing USN) (P = 0.02) in the OA cohort (n = 40). The priming dose of LPS used for these experiments (10 ng/ml) was below the lowest serum concentration of the OA cohort (median 47.09, range 14.43-81.36 ng/m1). Priming doses of LPS and HA fragments alone did not elicit an inflammatory response. However, primed with LPS, HA fragments produced large dose-dependent increases in IL-1 beta that were inhibitable by CS. CS did not inhibit caspase-1 activity but in physiologically achievable concentrations, attenuated NF-kappa B activity induced by either the TLR4 (LPS 1000 ng/ml) or TLR2 agonists alone or in combination with HA fragments. LPS induced and CS significantly reduced activity of canonical NF-kappa B transcription factors, p65, p50, c-Rel and Re1B.
Conclusions: Subinflammatory concentrations of pathogenic (LPS, listeria) and damage associated (HA) molecules interact to induce macrophage-related inflammation. CS works upstream of the inflammasome by inhibiting activation of NF-kappa B transcription factors. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
引用本文： . . 华西虚拟期刊, 2000, 1(1): 166-174-. doi: 10.1016/j.joca.2016.08.012 复制