PS3, A Semisynthetic beta-1,3-Glucan Sulfate, Diminishes Contact Hypersensitivity Responses Through Inhibition of L- and P-Selectin Functions

Abstract

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.