Immunosuppression by arsenic: a comparison of cathepsin L inhibition and apoptosis.
Arsenicals are toxicants and carcinogens to which large numbers of people risk exposure by contaminated water, air pollution or industrial contact. Several animal studies have determined that inorganic arsenicals are immunotoxic, but the mechanism of immune suppression is not clear. In this study, we show that trivalent arsenic inhibits enzymatic activity of the lysosomal protease cathepsin L (CathL) in the murine antigen-presenting B cell line TA3. CathL plays an important role in antigen processing, the mechanism by which antigen-presenting cells cleave foreign protein antigens to peptides for stimulating a T cell response. Deficient proteolysis may lead to diminished immune responses. Arsenite suppressed enzymatic activity within TA3 cells after 4 h exposure without affecting cell viability. Kinetic analyses revealed that the chemical was a reversible, partially noncompetitive inhibitor of CathL with a Ki of 120 microM. However, an 18 h arsenite exposure triggered 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 within 18 h, and early stages of apoptosis began by 4 h. These findings suggest that apoptosis may be an important mechanism for arsenic-induced immunosuppression.
Harrison
M T
MT
Department of Microbiology and Immunology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA. mtharris@hsc.vcu.edu
McCoy
K L
KL
D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000097:blood / Q000633:toxicity*; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000502:physiology; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; D001151:Arsenic