Synthetic polysulfated hyaluronic acid is a potent inhibitor for tumor necrosis factor production

Nan-Shan Chang, C. Intrieri, J. Mattison, G. Armand

研究成果: Article同行評審

27 引文 斯高帕斯(Scopus)


Based on the premise that naturally occurring glycosaminoglycans could serve as building blocks for synthesizing nontoxic drugs for suppression of tumor necrosis factor (TNF) production by inflammatory cells, we have chemically modified hyaluronic acid (HA) and tested its effects in blocking TNF-α and TNF-β production in vitro. HA was chosen mainly for its structural simplicity, nonimmunogenicity, and readiness for chemical modifications. When HA was chemically polysulfated to a sulfate/hexosamine molar ratio of 3.9, the sulfated HA, was shown to be a potent inhibitor of TNF-α production in lipopolysaccharide (LPS)- or interferon-γ-activated THP-1 cells. For example, a concentration of HA(s) as low as 10 ng/ml reduced TNF-α production in LPS-activated THP-1 cells more than 50%, whereas achieving a similar extent of reduction required 50 μg/ml native HA. By decreasing the extent of polysulfation, the inhibitory effect of HA(s) on TNF-α production was diminished. Other chemical modifications, including deacetylation, thiolation, or reduction of the carboxylic groups, could not increase the efficacy of HA in suppression of TNF-α production. Naturally polysulfated glycosaminoglycans, such as chondroitin sulfates, keratan sulfate, heparan sulfate, and heparin, failed to inhibit TNF-α production. HA(s) also restricted TNF-β (lymphotoxin) secretion in an Epstein-Barr virus-transformed B cell line, Roha-9, which constitutively produces TNF-β. HA(s) had no inhibitory effect on the proliferation of THP-1 or Roha-9 cells, which would account for the reduced TNF-α or TNF-β production. Furthermore, time-course metabolic labeling studies revealed that HA(s) could not restrict overall protein synthesis and secretion in THP-1 cells. However, HA(s) increased complement C1q secretion in THP-1 in a dose-dependent manner, but it had no effect on biosynthesis of complement C1 inhibitor, factor D, and Fcγ receptor type II (FcγRII). These results indicate that HA(s) selectively restricts the production of TNF-α, TNF-β, and probably several other protein species.

頁(從 - 到)778-784
期刊Journal of Leukocyte Biology
出版狀態Published - 1994 一月 1

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cell Biology

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