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Title Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose
Publication Date
Date Accessioned
Degree PhD
Discipline/Department Pharmacology, Toxicology & Therapeutics
Degree Level doctoral
University/Publisher University of Kansas
Abstract Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. APAP is metabolized to a reactive metabolite that causes hepatotoxicity in a dose-dependent manner. A series of cascading intracellular events lead to cellular necrosis; this necrosis initiates a sterile inflammatory response which includes the production of multiple cytokines and chemokines that in turn recruit innate immune cells into the liver. Many of the inflammatory or corresponding anti-inflammatory mediators that are produced in this process have been linked to alterations in the subsequent injury as well as the injury resolution. This dissertation focuses on one particular inflammatory mediator, interleukin-1â (IL-1â), and its ability to modulate neutrophil priming, activation and hepatic recruitment. We show that mature IL-1â is produced during APAP overdose in a caspase dependent manner (Nalp3 inflammasome) which can be inhibited in vivo by a pan-caspase inhibitor, and that IL-1â is capable of activating neutrophils in vivo. However, the limited amount of IL-1â produced during APAP overdose is insufficient to activate or recruit neutrophils into the liver. In confirmation of these findings, genetic elimination of the components of the Nalp3 inflammasome or the IL-1 receptor does not alter APAP-induced injury or neutrophil recruitment. It has previously been shown that neutrophils do not participate in APAP-induced injury. This has been demonstrated in various ways, however, controversy arose when pretreatment of mice with neutropenia-inducing antibody resulted in protection from APAP toxicity. To further clarify this matter, CD18-deficient mice were subjected to APAP overdose, and in agreement with previous findings these mice were not protected from APAP overdose. Next we functionally characterized neutrophils during APAP overdose to further confirm that neutrophils do not participate in exacerbation of injury. Interestingly, during injury resolution neutrophils become activated especially in peripheral blood but did not have enhanced reactive oxygen priming in the liver. These findings were confirmed with NADPH oxidase deficient mice which had no alteration in injury resolution. Interestingly, these data were very similar to neutrophil function in human APAP overdose patients. These data indicate that activation of neutrophils might be critical for maintaining host defense during hepatic impairment. As a whole, this dissertation shows IL-1â is a minor participant in the sterile inflammatory response following APAP overdose, but this response is critical for neutrophil activation and eventual injury resolution.
Subjects/Keywords Toxicology; Acetaminophen; Il-1beta; Neutrophil
Contributors Jaeschke, Hartmut (advisor); Apte, Udayan (cmtemember); Levant, Beth (cmtemember); Reed, Gregory A. (cmtemember); Weinman, Steve A. (cmtemember)
Language en
Rights This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
Country of Publication us
Record ID handle:1808/10290
Repository ku
Date Retrieved
Date Indexed 2018-02-01
Issued Date 2012-08-31 00:00:00

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…inflammation in the mechanism of APAP-induced liver injury is highly controversial (Jaeschke 2008). The objective of these studies was to determine if the formation of IL1β is a critical event in toxicity and if the production of IL-1β modulates…

…x29;. Thus, some initial hepatocellular injury must occur to initiate the inflammatory response which may then modulate the injury. Following APAP-induced toxic insult the formation of cytokines such as TNF-α, IL-1β and others, has been well described…

…antibodies attenuated cytokine and chemokine (TNF-α, MCP-1, IL-6) formation (Antoine et al., 2009; Chen et al., 2009) supporting the hypothesis that HMGB1 is an important mediator of the inflammatory response after APAP overdose. Mice…

…interleukin-1α and IL-1β are critical mediators of APAP hepatotoxicity based on the observation that IL-1 receptor-deficient (IL-1R1-/-) mice are protected (Chen et al., 2007) and the reports that mice deficient in components of the Nalp3…

…and caspase-1 (Lamkanfi et al., 2009). Based on the reduced injury in Nalp3-/-, ASC-/- and caspase-1-/- mice, it was concluded that processing of pro-IL-1β and pro-IL18 to the active, soluble cytokines is critical for APAP-induced liver…

…injury (Imaeda et al., 2009). The IL-1 receptor 1 (IL-1R1) and TLRs share a common signaling domain called the Toll-like/IL-1 Receptor (TIR) domain on the cytoplasmic side of the cell surface receptor as well as additional…

…adapter molecules all of which contain additional TIR domains (O’Neill and Bowie, 2008; Kenny and O’Neill, 2008). The lack of a cytoplasmic death domain in the IL-1R makes it impossible for IL-1α or β to directly induce cell death (Sims et…

IL-10, IL-6 and other cytokines and of cyclooxygenase products (Ju et al., 2002). IL-10 was shown to protect against APAP toxicity by downregulation of iNOS expression and peroxynitrite formation (Bourdi et al., 2002). In addition…