Pathogenic role of natural killer T and natural killer cells in acetaminophen-induced liver injury in mice is dependent on the presence of dimethyl sulfoxide.
Dimethyl sulfoxide (DMSO) is commonly used in biological studies to dissolve drugs and enzyme inhibitors with low solubility. Although DMSO is generally thought of as being relatively inert, it can induce biological effects that are often overlooked. An example that highlights this potential problem is found in a recent report demonstrating a pathogenic role for natural killer T (NKT) and natural killer (NK) cells in acetaminophen-induced liver injury (AILI) in C57Bl/6 mice in which DMSO was used to facilitate acetaminophen (APAP) dissolution. We report that NKT and NK cells do not play a pathologic role in AILI in C57Bl/6 mice in the absence of DMSO. Although AILI was significantly attenuated in mice depleted of NKT and NK cells prior to APAP treatment in the presence of DMSO, no such effect was observed when APAP was dissolved in saline. Because of this unexpected finding, the effects of DMSO on hepatic NKT and NK cells were subsequently investigated. When given alone, DMSO activated hepatic NKT and NK cells in vivo as evidenced by increased NKT cell numbers and higher intracellular levels of the cytotoxic effector molecules interferon-gamma (IFN-gamma) and granzyme B in both cell types. Similarly, when used as a solvent for APAP, DMSO again increased NKT cell numbers and induced IFN-gamma and granzyme B expression in both cell types.


CONCLUSIONS
These data demonstrate a previously unappreciated effect of DMSO on hepatic NKT and NK cells, suggesting that DMSO should be used cautiously in experiments involving these cells.
Masson
Mary Jane
MJ
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Carpenter
Leah D
LD
Graf
Mary L
ML
Pohl
Lance R
LR
D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques / Q000379:methods; D056486:Chemical and Drug Induced Liver Injury; D004121:Dimethyl Sulfoxide / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D053804:Granzymes / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008107:Liver Diseases / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015203:Reproducibility of Results; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D007371:Interferon-gamma; D053804:Granzymes; D004121:Dimethyl Sulfoxide