Delta(9)-tetrahydrocannabinol selectively increases aspartyl cathepsin D proteolytic activity and impairs lysozyme processing by macrophages

Delta(9)-tetrahydrocannabinol (THC) causes an antigen-dependent defect in t he ability of macrophages to activate helper T cells, and this drug-induced impairment is mediated through the peripheral CB2 receptor. Various requir ements for the processing of the antigen, lysozyme, were examined to determ ine where along the pathway THC exerts its influence. A THC-exposed macroph age hybridoma inefficiently stimulated interleukin-2 secretion by a helper T cell hybridoma in response to native lysozyme and its reduced form, sugge sting that disulfide bond reduction was unaffected. Cell surface expression of major histocompatibility complex class II molecules was normal on THC-e xposed macrophages. The drug-exposed macrophages also competently presented a lysozyme peptide to the T cells. indicating that the class II molecules were functional. The proteolytic activity of two thiol cathepsins was unalt ered, but aspartyl cathepsin D activity was significantly increased in THC- exposed macrophages. Thus, selective up-regulation of aspartyl cathepsin ac tivity accompanied the deficiency in lysozyme processing and may contribute , at least in part, to the antigen-dependent processing defect in THC-expos ed macrophages. (C) 2000 International Society for Immunopharmacology. Publ ished by Elsevier Science Ltd. All rights reserved.