P-106 Cytokine expression in the liver of primary biliary cirrhosis

Nagano, Tomohisa

doi:10.1016/0928-4346(95)90402-s

Cited by 46 publications

(58 citation statements)

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“…27 Defects may be present in 1 or more of these pathways in PBC patients that could be the basis of enhanced cytokine synthesis. Furthermore, the monocyte PAMP-induced cytokine production observed in our study appears compatible with previously obtained data [28][29][30][31][32] that implicate a significant role of Th-1 cytokines in the pathogenesis of PBC. We note, however, that Th-2 cytokines, such as IL-5, IL-6, and IL-10, also have been detected in PBC livers, 29,31 indicating that both Th-1 and Th-2 cytokines, possibly during different stages of the disease, might be involved in the pathogenesis of PBC.…”

Section: Discussionsupporting

confidence: 82%

Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis

et al. 2005

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The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper-responsive innate immune system to pathogen-associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age-matched healthy controls and stimulated such cells in vitro with defined ligands for toll-like receptor (

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Section: Discussionsupporting

confidence: 82%

Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis

et al. 2005

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“…This technique pinpointed the target sites for specimen collection and allowed us to investigate the gene expression of cytokines and TLRs in each specific liver area. Although several studies have analyzed cytokine expression in liver of PBC patients, [1][2][3][4][5][6][7] this is the first study to measure the steady-state expression levels of cytokines and TLRs in early stages of PBC within separate liver microenvironments of the portal tract and liver parenchyma. Th1 cells are important for the pathogenesis of various autoimmune diseases, 29 whereas Th2 cells contribute to allergic diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Since cytokines are pivotal factors regulating the inflammatory responses prevalent in many autoimmune disorders, the roles of cytokines have been previously investigated in the pathogenesis of PBC. [1][2][3][4][5][6][7] Despite these inquiries, the significance of each cytokine in the microenvironment of the liver remains elusive. Furthermore, several reports suggest that infectious agents may also be involved in the pathogenesis of PBC.…”

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confidence: 99%

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

Takii

Nakamura

Ito

et al. 2005

Laboratory Investigation

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The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-a, -b, -c, interleukin (IL)-1b, -4, -6, -10, -12p40, -18, tumor necrosis factor-a) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-a, -b and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-a, -b) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-a is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-b and TLR-3. Furthermore, the level of IFN-a mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC. Laboratory Investigation (2005) 85, 908-920.

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“…17 A potential mechanism for the cholestasis-associated effects on both fatigue and sleep is suggested by the observation that, in cholestatic animal models, changes in brain inflammatory cytokine levels (possibly resulting from the recently demonstrated increase in central nervous system infiltrating cytokine releasing mononuclear seen in such animals 18 ) are strongly linked to fatigue-like behavior. Interleukin-6 is an inflammatory cytokine present at elevated levels in human liver with PBC 19,20 and is excessively released by both cultured biliary epithelial cells in response to hydrophobic bile acids of the type retained in the liver in cholestasis 21 and spontaneously by PBMC from patients with PBC. 22 Interleukin-6 plays a key role in controlling circadian sleep patterns and promoting fatigue 23 and is elevated (together with tumor necrosis factor alpha and interleukin-1) in a number of conditions associated with daytime somnolence and fatigue of non-liver origin.…”

Section: Discussionmentioning

confidence: 99%

Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence

et al. 2006

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A significant proportion of patients with primary biliary cirrhosis (PBC) suffer from severe fatigue. The aim of this study was to characterize patterns of daytime sleep in patients with PBC (using both objective and subjective assessment approaches) and to study the association between sleep abnormality and fatigue severity. Fatigue severity was assessed in 48 female subjects with PBC (using a disease-specific quality of life instrument (the PBC-40) and a generic fatigue measure (Fatigue Impact Scale [FIS]) as well as 48 case-matched normal controls. All participants also completed the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS, which assesses daytime hypersomnolence). Objective sleep assessment was performed using accelerometry over 7 days. Global sleep quality assessed by the PSQI was significantly lower in the PBC group compared to controls (P < .0001). ESS scores were significantly higher in patients with PBC than controls (P ‫؍‬ .0001), suggesting significantly greater daytime somnolence in the patients with PBC. Objective sleep assessment confirmed that subjects with PBC were sleeping on average almost twice as long as controls during the daytime. Both degree of daytime somnolence (ESS) and actual daytime sleep activity (accelerometry) correlated strongly with fatigue severity in the patient group (r 2 ‫؍‬ 0.5, P < .0001 and r 2 ‫؍‬ 0.2, P < .01, respectively).

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P-106 Cytokine expression in the liver of primary biliary cirrhosis

Cited by 46 publications

References 0 publications

Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis

Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence

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