Type III Interferon Induces Distinct SOCS1 Expression Pattern that Contributes to Delayed but Prolonged Activation of Jak/STAT Signaling Pathway: Implications for Treatment Non-Response in HCV Patients
Bibliographic record
Abstract
Suppressor of cytokine signaling 1 (SOCS1) has long been thought to block type I interferon signaling. However, IFN-λ, a type III IFN with limited receptor expression in hepatic cells, efficiently inhibits HCV (Hepatitis C virus) replication in vivo with potentially less side effects than IFN-α. Previous studies demonstrated that type I and type III activated Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway differently, with delayed but prolonged activation by IFN-λ stimulation compared to IFNα/β. However, the molecular mechanisms underlying this observation is not well understood. Here, we found that there are distinct differences in SOCS1 expression patterns in Huh-7.5.1 cells following stimulation with IFN-α and IFN-λ. IFN-λ induced a faster but shorter expression of SOCS1. Furthermore, we confirmed that SOCS1 over-expression abrogates anti-HCV effect of both IFN-α and IFN-λ, leading to increased HCV RNA replication in both HCV replicon cells and JFH1 HCV culture system. In line with this, SOCS1 over-expression inhibited STAT1 phosphorylation, attenuated IFN-stimulated response elements (ISRE) reporter activity, and blocked IFN-stimulated genes (ISGs) expression. Finally, we measured SOCS1 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) with or without IFN-α treatment from 48 chronic hepatitis C patients and we found the baseline SOCS1 expression levels are higher in treatment non-responders than in responders before IFN-α treatment. Taken together, SOCS1 acts as a suppressor for both type I and type III IFNs and is negatively associated with sustained virological response (SVR) to IFN-based therapy in patients with HCV. More importantly, faster but shorter induction of SOCS1 by IFN-λ may contribute to delayed but prolonged activation of IFN signaling and ISG expression kinetics by type III IFN.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".