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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

4-Mer Hyaluronan Oligosaccharides Stimulate Inflammation Response in Synovial Fibroblasts in Part via TAK-1 and in Part via p38-MAPK

Author(s): G. M. Campo, A. Avenoso, A. D’Ascola, V. Prestipino, M. Scuruchi, G. Nastasi, A. Calatroni and S. Campo

Volume 20 , Issue 9 , 2013

Page: [1162 - 1172] Pages: 11

DOI: 10.2174/0929867311320090005

Price: $65


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.

Keywords: Hyaluronan, NF-kB, toll-like receptors, cytokines, RASF, p38-MAPK, TAK-1, 4-mer hyaluronan (HA), oligosaccharides, pro-inflammatory effects

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