Detection and analysis of intracytoplasmic cytokines in peripheral blood mononuclear cells in patients with drug-induced liver injury.
OBJECTIVE
Idiosyncratic immune response to drugs causes two types of liver injury, cholestasis or hepatitis. However, the underlying immune mechanisms of drug-induced liver injury are presently unclear.


METHODS
We examined the cytokine production of peripheral blood mononuclear cells (PBMCs) from 17 patients with drug-induced liver injury and healthy controls during their incubation with and without the drug by flow cytometry. We also analyzed the cytokine production in PBMCs from eight patients after stimulation with the drug-pulsed HepG2 lysates to examine the possibility that the drug or its metabolites conjugated with a putative molecule derived from HepG2 cells might be more immunogenic.


RESULTS
Among several cytokines produced by the drug or the drug-pulsed HepG2 lysates, interferon-gamma production from CD8+ cells was associated with hepatocellular injury, and tumor necrosis factor-alpha production from CD14+ cells was with cholestasis. Especially, the latter was apparent when the drug-pulsed HepG2 lysates were used as stimulants, suggesting that a complex consist of the drug, or its metabolite, and a putative molecule derived from HepG2 cells might be more immunogenic than the drug itself.


CONCLUSIONS
The analysis of intracytoplasmic cytokine in PBMCs after stimulation with the drug or the drug-pulsed HepG2 lysates is useful to analyze the immune mechanism underlying drug-induced liver injury.
Murata
Hiroyuki
H
The Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Shimizu
Yukihiro
Y
Okada
Kazuhiko
K
Higuchi
Kiyohiro
K
Watanabe
Akiharu
A
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000032:analysis*; D003593:Cytoplasm / Q000737:chemistry / Q000276:immunology; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry
D016207:Cytokines; D018950:Lipopolysaccharide Receptors