Dermatan sulfate activates nuclear factor-κb and induces endothelial and circulating intercellular adhesion molecule-1
Stanley F. Penc, … , Michael Detmar, Richard L. Gallo
Stanley F. Penc, … , Michael Detmar, Richard L. Gallo
Published May 1, 1999
Citation Information: J Clin Invest. 1999;103(9):1329-1335. https://doi.org/10.1172/JCI4742.
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Article

Dermatan sulfate activates nuclear factor-κb and induces endothelial and circulating intercellular adhesion molecule-1

Abstract

Proteoglycans (PGs) can influence cell behaviors through binding events mediated by their glycosaminoglycan (GAG) chains. This report demonstrates that chondroitin sulfate B, also known as dermatan sulfate (DS), a major GAG released during the inflammatory phase of wound repair, directly activates cells at the physiologic concentrations of DS found in wounds. Cultured human dermal microvascular endothelial cells exposed to DS responded with rapid nuclear translocation of nuclear factor-κB (NF-κB), increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, and increased ICAM-1 cell surface protein. Heparan sulfate and chondroitin sulfates A and C had no effect on activation of NF-κB or induction of ICAM-1. Inhibition of NF-κB activation blocked the effect of DS. The increase in cell surface ICAM-1 did not involve TNF-α or IL-1 release by endothelial cells, but it was facilitated by autocrine factors whose release was initiated by DS. The ICAM-1–inductive activity of DS was confirmed in vivo. Injection of DS, but not heparin or other chondroitin sulfates, into mice greatly increased circulating levels of soluble ICAM. These data provide evidence that DS, but not other GAGs, initiates a previously unrecognized cell signaling event that can act during the response to injury.

Authors

Stanley F. Penc, Bohdan Pomahac, Elof Eriksson, Michael Detmar, Richard L. Gallo

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DS activates NF-κB signaling. Activation of NF-κB and STAT signaling was...
DS activates NF-κB signaling. Activation of NF-κB and STAT signaling was measured by their translocation from endothelial cell cytosol to cell nuclei. (a) Measurement of NF-κB activation by electrophoretic mobility shift assay of nuclear extracts from endothelial cells treated for 0–120 minutes with 50 μg/mL pure DS, or 120 minutes with 2.5 ng/mL TNF-α (lane T). All extracts were mixed with 32P-labeled oligonucleotides containing the NF-κB binding site. The sample in lane B is identical to that in lane T, with the addition of a 50-fold excess of unlabeled oligonucleotide. (b) Immunostaining of endothelial cells with antibody ISGF3 specific for the STAT complex. (1) Cells treated with media alone for 30 minutes. (2) Cells treated with 50 μg/mL pure DS for 30 minutes. (3) Cells treated with 100 U/mL IFN-γ for 30 minutes.