COLCHICINE ALTERS THE QUANTITATIVE AND QUALITATIVE DISPLAY OF SELECTINS ON ENDOTHELIAL-CELLS AND NEUTROPHILS

Since colchicine-sensitive microtubules regulate the expression and to pographg of surface glycoproteins on a variety of cells, we sought evi dence that colchicine interferes with neutrophil-endothelial interacti ons by altering the number and/or distribution of selectins on endothe lial cells and neutrophils. Extremely low, prophylactic, concentration s of colchicine (IC50 = 3 nM) eliminated the E-selectin-mediated incre ment in endothelial adhesiveness for neutrophils in response to IL-1 ( P < 0.001) or TNF alpha (P < 0.001) by changing the distribution, but not the number, of E-selectin molecules on the surface of the endothel ial cells. Colchicine inhibited stimulated endothelial adhesiveness vi a its effects on microtubules since vinblastine, an agent which pertur bs microtubule function by other mechanisms, diminished adhesiveness w hereas the photoinactivated colchicine derivative gamma-lumicolchicine was inactive, Colchicine had no effect on cell viability, At higher, therapeutic, concentrations colchicine (IC50 = 300 nM, P < 0.001) also diminished the expression of L-selectin on the surface of neutrophils (but not lymphocytes) without affecting expression of the beta(2)-int egrin CD11b/CD18, In confirmation, L-selectin expression was strikingl y reduced (relative to CD11B/CD18) expression) on neutrophils from two individuals who had ingested therapeutic doses of colchicine. These r esults suggest that colchicine may exert ifs prophylactic effects on c ytokine-provoked inflammation by diminishing the qualitative expressio n of E-selectin on endothelium, and its therapeutic effects by diminis hing the quantitative expression of L-selectin on neutrophils.