PS3, a semisynthetic beta-1,3-glucan sulfate, diminishes contact hypersensitivity responses through inhibition of L- and P-selectin functions.
Leukocyte extravasation is initiated by an interaction of selectin adhesion molecules and appropriate carbohydrate ligands. Targeting those interactions seems a promising approach to treat chronic inflammation. We developed a beta-1, 3-glucan sulfate (PS3) with inhibitory activity toward L and P-selectins under static conditions. Here, detailed investigation showed inhibition of P- and L-selectins, but not E-selectin under flow conditions (relative reduction of interaction with appropriate ligands to 34.4+/-16.6, 8.5+/-3.6, or 99.5+/-9.9%, respectively, by PS3 for P-, L- or E-selectin). Intravital microscopy revealed reduction of leukocyte rolling in skin microvasculature from 22.7+/-5.0 to 12.6+/-4.0% after injection of PS3. In the next experiments, mice were sensitized with 2,4,-dinitrofluorobenzene (DNFB), and lymphocytes were transferred into syngeneic recipients, which were challenged by DNFB. Inflammatory responses were reduced when immunity was generated in mice treated with PS3 or in L-selectin-deficient mice. No effect was observed when L-selectin-deficient donor mice were treated with PS3, further suggesting that PS3 acted primarily through inhibition of L-selectin. Elicitation of a contact hypersensitivity response was reduced in P-selectin-deficient and in PS3-treated mice. Again, PS3 had no effect in P-selectin-deficient mice. PS3 is a potent P- and L-selectin inhibitor that may add to the therapy of inflammatory diseases.
Alban
Susanne
S
Pharmaceutical Institute, Christian-Albrechts University, Kiel, Germany.
Ludwig
Ralf J
RJ
Bendas
Gerd
G
Schön
Michael P
MP
Oostingh
Gertie J
GJ
Radeke
Heinfried H
HH
Fritzsche
Juliane
J
Pfeilschifter
Josef
J
Kaufmann
Roland
R
Boehncke
Wolf-Henning
WH
D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000276:immunology / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005936:Glucans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019041:L-Selectin / Q000187:drug effects* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000187:drug effects* / Q000378:metabolism; D047071:beta-Glucans / Q000494:pharmacology / Q000627:therapeutic use
D000485:Allergens; D005936:Glucans; D019007:P-Selectin; C532541:PS3 glucan; D047071:beta-Glucans; D019041:L-Selectin; C033363:beta-1,3-glucan; D004139:Dinitrofluorobenzene