Bibliographic record
Abstract
BACKGROUND AND AIMS: Human Biliary Epithelial Cells (BECs) express TLRs and NOD proteins, which rapidly detect potential pathogens in the bile or portal venous blood flow.We characterized the TLR and NOD expression and function in primary human BECs in end-stage chronic inflammatory liver disease of various etiologies.We also examined the expression of IFN-γ and TNF-α, which have been shown to modulate TLR and NOD expression in various cells, and assessed their effect on TLR and NOD signaling in human BECs.METHODS: Primary extra-and intra-hepatic BECs were obtained from patients undergoing partial liver resection or liver transplantation for end-stage chronic inflammatory liver disease (chronic HBV and HCV infection, PBC, PSC, AIH, alcoholic and cryptogenic).IFNγ and TNF-α expression in whole liver tissue, and TLR and NOD expression in isolated primary BECs were determined by northern blots, real-time RT-PCR, western blots and immunocytochemistry.Flow cytometry for incorporated LPS particles and ELISAs for secreted IL-6, IL-8 and MCP-1 protein after stimulation with specific TLR and NOD ligands were used for functional studies.Immortalized BECs were used for functional NF-kB reporter assays and over-expression studies.RESULTS: Whole liver tissue of patients with end-stage chronic inflammatory liver disease showed increased IFN-γ and TNF-α expression as compared to healthy liver tissue.Freshly isolated BECs of these patients exhibited enhanced expression of IFN-γ dependent genes (CXCL9, CXCL10, CXCL11), suggesting biological effects in vivo.These BECs showed increased TLR and NOD expression as compared to BECs of control patients and were more sensitive to stimulation with specific TLR and NOD ligands.This appeared to be independent from the etiology of the chronic liver disease, arguing against a disease-specific observation.The enhanced TLR and NOD expression decreased significantly after short-time culture without Th1 cytokines, suggesting that enhanced TLR and NOD signaling in end-stage chronic inflammatory liver disease might be a general secondary phenomenon of chronic liver inflammation.In vitro stimulation experiments confirmed that IFN-γ and TNF-α induced TLR and NOD expression and function after stimulation with specific ligands.Th1 cytokine-primed BECs showed enhanced IRF-1 expression, which has been shown to promote NOD signaling.CONCLUSIONS: Pro-inflammatory Th1 cytokines in end-stage chronic inflammatory liver disease reversibly promote TLR and NOD protein expression and function in affected BECs.Subsequently increased pro-inflammatory innate immune responses might contribute to perpetuation of chronic liver inflammation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.776 | 0.680 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".