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Cytokine gene expression and production by human LPS‐stimulated mononuclear cells are inhibited by sulfated heparin‐like semi‐synthetic derivatives
Author(s) -
Gori A. M.,
Attanasio M.,
Gazzini A.,
Rossi L.,
Lucarini L.,
Miletti S.,
Chini J.,
Mai M.,
Abbate R.,
Gensini G. F.
Publication year - 2004
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2004.00866.x
Subject(s) - heparin , sulfation , peripheral blood mononuclear cell , cytokine , lipopolysaccharide , tumor necrosis factor alpha , chemistry , heparan sulfate , polysaccharide , biochemistry , microbiology and biotechnology , biology , in vitro , immunology
Summary. Background : The K5 polysaccharide obtained from Escherichia coli strain 010:K5:H4 is a polymer of the disaccharidic unit formed by D‐glucuronic acid and N‐acetylglucosamine. This structure is akin to N‐acetylheparosan, the precursory polymer of heparin and of heparan sulfate. This structural affinity with N‐acetylated heparin and with de‐sulfated heparin makes the K5 polysaccharide extremely useful for the preparation of sulfated heparin‐like semi‐synthetic derivatives. It has been demonstrated that heparins are able to inhibit tissue factor and cytokine production and expression by human monocytes. Objective : The aim of this study was to evaluate the effects of four different heparin‐like semi‐synthetic derivatives on inflammatory cytokine production and expression by human mononuclear cells. Results : The simultaneous addition of lipopolysaccharide (LPS; 0.2 and 10 µg mL −1 ) and the K5 polysaccharide did not inhibit interleukin (IL)‐1β, IL‐6 or tumor necrosis factor (TNF)‐α production by stimulated mononuclear cells. IL‐1β, IL‐6 and TNF‐α concentrations in supernatants of LPS‐stimulated mononuclear cells were not influenced by the addition of N,O‐sulfated K5 polysaccharide (K5‐N, OS) and epimerized N‐sulfated K5 polysaccharide (K5 NS epi) at 5 and 10 µg mL −1 , whereas the addition of epimerized N,O‐sulfated K5 polysaccharide (K5‐N, OS epi) (5 and 10 µg mL −1 ) and O‐sulfated K5 polysaccharide (K5‐OS) (5 and 10 µg mL −1 ) to LPS‐stimulated cells caused a significant dose‐dependent inhibition of IL‐1β, IL‐6 and TNF‐α. All sulfated heparin‐like semi‐synthetic derivatives did not influence the IL‐10 production by LPS‐stimulated mononuclear cells. In LPS‐stimulated cells (0.2 and 10 µg mL −1 ), K5‐OS or K5‐N, OS epi at 5 and 10 µg mL −1 markedly decreased TNF‐α mRNA expression. Conclusions : These results indicate that the sulfated heparin‐like semi‐synthetic derivatives K5‐OS and K5‐N, OS epi are able to inhibit both expression and production of inflammatory cytokines, whereas they do not influence the anti‐inflammatory cytokine IL‐10, suggesting a potential role for these products as modulators of inflammatory reactions.