Zinc at pharmacologic concentrations affects cytokine expression and induces apoptosis of human peripheral blood mononuclear cells.
OBJECTIVE
The present study examined the effect of zinc at concentrations of the apoptotic signaling pathway and immune function of peripheral blood mononuclear cells (PBMCs).


METHODS
PBMCs from healthy subjects were treated in vitro with various zinc concentrations to imitate different serum statuses of physiologic (2 to 15 microM) and pharmacologic (15 to 100 microM) concentrations to higher than 100 microM and analyzed their expressions of cytokines and apoptotically related factors.


RESULTS
Although a normal physiologic concentration of zinc had no effect on immunologic function or apoptosis of PBMCs, a pharmacologic concentration (100 microM) or higher affected both functions. Zinc decreased cell proliferation at concentrations higher than 100 microM and stimulated cytokine expression at concentrations of at least 100 microM. Further, at concentrations of at least 100 microM, apoptosis was induced, and expressions of caspase-3 and proapoptotic genes, including Fas (FasL) and c-fos, which trigger apoptosis through receptor-mediated extrinsic and mitochondrion-mediated apoptotic pathways, respectively, were increased. At concentrations at least 300 microM, expressions of antiapoptotic factors nuclear factor-kappaB, Bcl-2, and Bcl-X(L) were markedly decreased.


CONCLUSIONS
Zinc stimulates cytokine expression and induces apoptosis of PBMCs from healthy subjects only at concentrations equal to or greater than the serum pharmacologic range. Receptor-mediated extrinsic and mitochondrial-mediated intrinsic pathways are involved in this zinc-induced apoptosis.
Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. keeluch@kmu.edu.tw
Kee-Lung
KL
Chang
Thu-Ching
TC
Hung
Bau-Shan
BS
Hsieh
Yen-Hui
YH
Chen
Te-Fu
TF
Chen
Hsiao-Ling
HL
Cheng
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014131:Trace Elements / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D014131:Trace Elements; D048069:Tumor Necrosis Factors; D051020:bcl-X Protein; D012313:RNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015032:Zinc