Immunosuppression by arsenic: a comparison of cathepsin L inhibition and apoptosis

Arsenicals are toxicants and carcinogens to which large numbers of people r isk exposure by contaminated water, air pollution or industrial contact. Se veral animal studies have determined that inorganic arsenicals are immunoto xic, but the mechanism of immune suppression is not clear. In this study, w e show that trivalent arsenic inhibits enzymatic activity of the lysosomal protease cathepsin L (CathL) in the murine antigen-presenting B cell line T A3. CathL plays an important role in antigen processing, the mechanism by w hich antigen-presenting cells cleave foreign protein antigens to peptides f or stimulating a T cell response. Deficient proteolysis may lead to diminis hed immune responses. Arsenite suppressed enzymatic activity within TA3 cel ls after 4 h exposure without affecting cell viability. Kinetic analyses re vealed that the chemical was a reversible. partially noncompetitive inhibit or of CathL with a Ki Df 120 muM However, an 18 h arsenite exposure trigger ed massive cell death at concentrations that were substantially lower than those required for enzymatic inhibition. Morphological analysis and annexin V staining showed that arsenite-exposed TA3 cells underwent apoptosis with in 18 h, and early stages of apoptosis began by 4 h. These findings suggest that apoptosis may be an important mechanism for arsenic-induced immunosup pression. (C) 2001 Elsevier Science B.V. All rights reserved.