Abstract.
Objective:
This study investigated the inhibitory mechanism of hyaluronan (HA) on lipopolysaccharide (LPS)-stimulated production of proinflammatory cytokines in U937 macrophages.
Methods:
HA was added to U937 macrophage cultures in the presence of LPS, with or without pretreatment with anti-intercellular adhesion molecule-1 (ICAM-1) antibody. Secreted levels of tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 were determined by enzyme-linked immunosorbent assay. The phosphorylation of nuclear factor (NF)-κB, IκBα, and mitogen-activated protein kinases (MAPKs) was analyzed by immunoblotting.
Results:
LPS stimulated production of TNFα, IL-1β, and IL-6. In contrast to 800 kDa HA, 2700 kDa HA at 1 mg/ml inhibited LPS-induced cytokine production. Anti-ICAM-1 antibody blocked the effects of HA on the LPS actions on U937 cells. LPS activated NF-κB and MAPK pathways, whereas HA down-regulated p65 NF-κB and IκBα phosphorylation by LPS without affecting MAPKs. Inhibition studies revealed the requirement of NF-κB for LPS-stimulated cytokine production. Anti-ICAM-1 antibody reversed the inhibitory effects of HA on phosphorylation of p65 NF-κB and IκBα.
Conclusion:
HA of intrinsic molecular weight suppresses LPS-stimulated production of proinflammatory cytokines via ICAM-1 through down-regulation of NF-κB and IκB. Exogenous HA injected into arthritic joints could act as an anti-NF-κB agent by the mechanism demonstrated in the present study.
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Received 23 September 2006; returned for revision 12 October 2006; accepted J. Di Battista 18 December 2006
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Yasuda, T. Hyaluronan inhibits cytokine production by lipopolysaccharide-stimulated U937 macrophages through down-regulation of NF-κB via ICAM-1. Inflamm. res. 56, 246–253 (2007). https://doi.org/10.1007/s00011-007-6168-5
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DOI: https://doi.org/10.1007/s00011-007-6168-5