Title:4-Mer Hyaluronan Oligosaccharides Stimulate Inflammation Response in Synovial Fibroblasts in Part via TAK-1 and in Part via p38-MAPK
Volume: 20
Issue: 9
Author(s): G. M. Campo, A. Avenoso, A. D’Ascola, V. Prestipino, M. Scuruchi, G. Nastasi, A. Calatroni and S. Campo
Affiliation:
Keywords:
Hyaluronan, NF-kB, toll-like receptors, cytokines, RASF, p38-MAPK, TAK-1, 4-mer hyaluronan (HA), oligosaccharides, pro-inflammatory effects
Abstract: 4-mer hyaluronan (HA) oligosaccharides stimulate pro-inflammatory effects in different cell types by interacting
with both the toll-like receptor-4 (TLR-4) and -2 (TLR-2). This interaction induces the activation of the transforming
growth factor activated kinase-1 (TAK-1) that activates the nuclear factor kappaB (NF-kB) either directly and/or through
the activation of p38-mitogen-activated protein kinase (p38-MAPK). This in turn induces the transcription of proinflammatory
mediators that prime inflammation. Our aim was to investigate the involvement of TAK-1 and p38-MAPK
in 4-mer HA oligosaccharide-induced inflammatory response in mouse synovial fibroblasts obtained from normal DBA/J1
mice (NSF) and from mice subjected to collagen-induced arthritis (CIA). Treatment of NSF and rheumatoid arthritis
synovial fibroblasts (RASF) with 4-mer HA showed a marked up-regulation of TLR-4, TLR-2, TAK-1 and p38-MAPK
mRNA expression and of the related proteins, as well as NF-kB activation. High levels were also detected of TNF-α, IL-
1β, MMP-13 and iNOS. Treatment of NSF and RASF, previously stimulated with 4-mer HA oligosaccharides, with TAK-
1 and/or p38-MAPK specific inhibitors significantly reduced all the parameters, although the inhibitory effect of p38-
MAPK was less effective than that of TAK-1. The addition of CD44 antibody to both NSF and RASF showed that CD44
was not involved in 4-mer HA-induced inflammation.
