In vitro exposure to malondialdehyde-acetaldehyde adducted protein inhibits cell proliferation and viability.
BACKGROUND
Circulating antibodies against malondialdehyde-acetaldehyde (MAA) haptenated proteins are increased significantly in patients with alcohol-induced cirrhosis and hepatitis and are associated with severity of liver damage. Additionally, MAA haptenated proteins are highly immunogenic without the use of adjuvant and have been suggested to induce autoreactive responses. The mechanism of this immunogenicity is currently unknown but may be mediated by cell death in a similar manner as other autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, myositis, and Sjögren's disease.


METHODS
Antigen-presenting cells, lymphocytes, and hepatocytes were exposed to different levels of MAA haptenated hen egg lysozyme and assessed by [3H]thymidine incorporation and (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) conversion for viability.


RESULTS
The cells investigated in this study were those that potentially may be involved in the development of autoimmune liver damage; they include antigen-presenting cells, lymphocytes, and cells of the liver itself. Each cell type was found to be sensitive to MAA haptenated protein-induced cell death at levels between 690 microM (10 microg/ml) and 6.9 mM (100 microg/ml), which may be found locally after chronic ethanol consumption. Antigen-presenting cells (macrophage and B cells) were found to be activated at concentrations just under those levels associated with cell death.


CONCLUSIONS
A dose response to MAA haptenated protein-induced cell death is seen in antigen-presenting cells, lymphocytes, and hepatocytes in vitro. Recent reports have associated both apoptotic and necrotic cell death with the development of autoimmune disease; thus, it is possible that this may be one mechanism by which in vivo immunogenicity is mediated by aldehyde haptenated proteins.
Willis
Monte S
MS
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA. montewillis@juno.com
Klassen
Lynell W
LW
Tuma
Dean J
DJ
Sorrell
Michael F
MF
Thiele
Geoffrey M
GM
D000079:Acetaldehyde / Q000737:chemistry*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006241:Haptens / Q000737:chemistry / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D009113:Muramidase / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D006241:Haptens; D008934:Mitogens; D008315:Malondialdehyde; D009113:Muramidase; D000079:Acetaldehyde