Modulation of human natural killer cell function by L-leucine methyl ester: monocyte-dependent depletion from human peripheral blood mononuclear cells.
L-leucine methyl ester (Leu-OMe) causes lysosomal disruption and death of human monocytes (M phi). In addition, Leu-OMe removed natural killer cell (NK) activity from human peripheral mononuclear cells (PBM). Thus, a brief preincubation of PBM with Leu-OMe (greater than 1 mM) caused irreversible loss of NK function as assessed by the lysis of K562 targets. By contrast, a variety of other amino acid methyl esters, including L-glutamic dimethyl ester, L-valine methyl ester, and L-isoleucine methyl ester caused reversible inhibition of NK activity in a manner that was similar to other lysosomotropic agents such as chloroquine and ammonium chloride, but did not cause irreversible loss of all NK function. Leu-OMe appeared to cause actual removal of NK effector cells from PBM, because K562 target binding cells, Leu-11b+ lymphocytes, and OKM1+ lymphocytes were depleted. If M phi were removed from PBM before the incubation, Leu-OMe caused only reversible inhibition of NK function in a manner similar to that observed with other amino acid methyl esters. Upon the addition of freshly isolated M phi, polymorphonuclear leukocytes, or sonicates of these cells to M phi-depleted lymphocyte populations, irreversible ablation of NK function was again observed as a result of Leu-OMe exposure. After in vitro culture, M phi lost their susceptibility to Leu-OMe toxicity and the ability to mediate the irreversible deletion of NK cells resulting from Leu-OMe incubation. These results indicate that in the absence of M phi, Leu-OMe and a variety of other amino acid methyl esters are reversible inhibitors of NK function. However, Leu-OMe is unique in that it can interact with M phi or granulocytes to effect an irreversible loss of NK activity from human peripheral blood lymphocytes.
D000328:Adult; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004351:Drug Resistance; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
D007166:Immunosuppressive Agents; C030365:leucine methyl ester; D007930:Leucine