title: Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice.
abstract: Hepatic injury induced by various toxic agents, including acetaminophen (APAP), has been attributed, in part, to the production of proinflammatory cytokines and other mediators by resident Kupffer cells within the liver. However, recent evidence from our laboratory has demonstrated that hepato-protective factors, such as interleukin (IL)-10 and cyclooxygenase-derived mediators, are also upregulated in response to hepatic damage to help protect against exacerbated injury, and Kupffer cells have been suggested to be a source of these modulatory factors. In other models, Kupffer cells also serve important regulatory functions in pathophysiological states of the liver. Therefore, we reevaluated the role of Kupffer cells in a murine model of APAP-induced liver injury using liposome-entrapped clodronate (liposome/clodronate) as an effective Kupffer cell-depleting agent. We show that in contrast to pretreatment of mice with a widely used macrophage inhibitor, gadolinium chloride, which did not deplete Kupffer cells but moderately protected against APAP-induced hepatotoxicity as reported previously, the intravenous injection of liposome/clodronate caused nearly complete elimination of Kupffer cells and significantly increased susceptibility to APAP-induced liver injury as compared with mice pretreated with empty liposomes. This increased susceptibility was apparently unrelated to the metabolism of APAP since liposome/clodronate pretreatment did not alter APAP-protein adduct levels. Instead, Kupffer cell depletion by liposome/clodronate led to significant decreases in the levels of hepatic mRNA expression of several hepato-regulatory cytokines and mediators, including IL-6, IL-10, IL-18 binding protein and complement 1q, suggesting that Kupffer cells are a significant source for production of these mediators in this model. Our findings indicate that, in addition to their protoxicant activities, Kupffer cells can also have an important protective function in the liver through the production of a variety of modulatory factors which may counteract inflammatory responses and/or stimulate liver regeneration.
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. Cynthia.Ju@uchsc.edu
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ju
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Reilly
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bourdi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Radonovich
authors.forename: John N
authors.initials: JN
authors.lastname: Brady
authors.forename: John W
authors.initials: JW
authors.lastname: George
authors.forename: Lance R
authors.initials: LR
authors.lastname: Pohl
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004002:Clodronic Acid / Q000494:pharmacology; D015922:Complement C1q / Q000096:biosynthesis; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008081:Liposomes; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D008081:Liposomes; D012333:RNA, Messenger; D004002:Clodronic Acid; D000082:Acetaminophen; D015922:Complement C1q; D005682:Gadolinium; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000410:Alanine Transaminase; C038958:gadolinium chloride