부산대학교 도서관

CHAPTER Ⅱ. Nicotine attenuates concanavalin A-induced liver injury in mice by regulating the α7-nicotinic acetylcholine receptor in Kupffer cellsABSTRACTNicotine, a potent parasympathomimetic alkaloid, manifests anti-inflammatory properties by activating nicotinic acetylcholine receptors (nAchRs). In this study, we evaluated the effects of nicotine on concanavalin A (ConA)-induced autoimmune hepatitis. Nicotine (0.5 and 1 mg/kg) was intraperitoneally administered to BALB/c mice and mice were intravenously injected with ConA (15 mg/kg) to induce hepatitis. The results showed that nicotine treatment ameliorated pathological lesions in livers and significantly suppressed the expression of pro-inflammatory cytokines in the livers. Such effects were mediated by inhibiting the nuclear factor-kappa B (NF-κB) signaling in livers. Interestingly, nicotine inhibited the ConA-induced inflammatory response in primary cultured Kupffer cells (KCs) but did not alter the proliferation of splenocytes. The protective effects of nicotine against ConA-induced hepatitis were abolished in KC-depleted mice, indicating the requirement of KCs in this process. Additionally, the expression of α7-nAchR on KCs was dramatically increased by nicotine treatment, and the protective effects of nicotine on ConA-induced liver injury were significantly suppressed by treatment with methyllycaconitine (MLA), a specific α7-nAchR antagonist. Consistently, in primary cultured KCs, the activation of NF-κB signaling was also regulated by nicotine treatment. This study suggests that nicotine increases α7-nAchR-mediated cholinergic activity in KCs resulting in decrease of ConA-induced autoimmune hepatitis through inhibiting NF-κB signaling.
CHAPTER Ⅳ. Toll-like receptor-7 signaling in Kupffer cells exacerbates concanavalin A-induced liver injury in miceABSTRACTConcanavalin A (ConA) is a plant lectin that can induce immune-mediated liver damage, which is currently a widely accepted model that can mimic clinical acute hepatitis and immune-mediated liver injury in humans. Toll-like receptor-7 (TLR7) is a member of the TLR family and plays a key role in pathogen recognition and innate immune activation. The aim of this study is to examine the role of TLR7 in the pathogenesis of ConA-induced liver injury. Acute liver injury was induced by intravenously injected with ConA in WT (wild-type) and TLR7 KO (knockout) mice. The results showed that the attenuated liver injury in TLR7-deficient mice, as indicated by increased survival rate, decreased aminotransferase levels and reduced pathological lesions, was associated with decreased release of pro-inflammatory cytokines in the livers. Consistently, a significantly decreased proliferation of CD4+ T cell was detected in ConA-stimulated TLR7-deficient splenocytes, but not in CD3/CD28 stimulated TLR7-deficient CD4+ T cells. Moreover, TLR7 deficiency in KCs specifically suppresses the expression of TNF-α, and depletion of KCs abolished the detrimental role of TLR7 in the ConA-induced liver injury. Therefore, these results demonstrated that TLR7 can regulate the expression of TNF-α (tumor necrosis factor-α) in KCs, which is necessary for the full progression of ConA-induced liver injury.
CHAPTER Ⅲ. Mincle signaling exacerbates acetaminophen-induced liver injury by promoting Kupffer cell activation in miceABSTRACTAcetaminophen (APAP) overdose has become a major cause of acute liver failure (ALF) and hepatotoxicity. Mincle (Macrophage-inducible C-type lectin) can recognize SAP130 (spliceosome associated protein 130), an endogenous ligand released from necrotic cells, and plays a critical role in mediating immune responses. This study aims to examine the role of Mincle in APAP-induced liver injury. Acute liver injury was induced in WT (wild-type) and Mincle KO (knockout) mice by APAP injection. The hepatic expressions of Mincle, SAP130, and Mincle signaling intermediate (Syk) were markedly up-regulated following the APAP challenge. Mincle KO mice showed attenuated liver injury, as indicated by reduced pathological lesions, decreased aminotransferase levels, down-regulated inflammation and decreased neutrophil infiltration. Consistently, blockade of Syk signaling ameliorated APAP-induced liver injury. Most importantly, Kupffer cells (KCs) were identified as the main cellular source of Mincle. The depletion of KCs abolished the detrimental role of Mincle, and the adoptive transfer of WT KC to Mincle KO mice partially reversed the hyporesponsiveness to APAP-induced liver injury. Furthermore, the expression levels of interleukin (IL)-1β and neutrophil-attractant CXC chemokines were significantly lower in KCs isolated from APAP-treated Mincle KO mice compared with those from WT mice. Similar results were observed also in primary Mincle KO KCs treated with TDB (trehalose-6,6-dibehenate, a Mincle ligand) or in conditioned media obtained from APAP-treated hepatocytes. Taken together, these results demonstrated that Mincle can regulate the inflammatory response of KCs, which is necessary for the complete progression of liver injury induced by APAP.