A100 PANCREASTATIN WORSENS INTESTINAL INFLAMMATION BY INDUCING CLASSICALLY ACTIVATED MACROPHAGES (M1) THROUGH SUPPRESSION OF STAT3
Bibliographic record
Abstract
Chromogranin-A (CHGA) levels are increased in inflammatory bowel disease (IBD) and murine models of colitis. CHGA is cleaved in several peptides including the immunoregulatory pancreastatin (PST: CHGA273-301), which encodes by CHGA exon-VII. Classically activated macrophages (M1) and signal transducer and activator of transcription (STAT) 3 play significant roles in the pathophysiology of IBD. Previously we showed that Chga-knockout mice (Chga-/-) exhibited a significant decrease in the severity of colitis correlated with a reduction of M1 activity. we aimed to investigate the activity of PST in patients with active ulcerative colitis (UC) and the underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis using Chga-/- mice to define the effect on macrophages activation and migration Serum and colonic protein levels of PST were quantified in Patients with UC & healthy individuals. Expression of CHGA Exon-VII expressing PST and its correlation with M1 markers (IL-1β, IL-6, TNF-α, MCP-1) and STAT3 levels were determined in human colonic tissues. Colitis was induced in Chga+/+ and Chga-/- mice by administrating DSS (5%, 5 days). PST treatment (2.5 mg/kg/day) or vehicle (Phosphate Buffered-Saline 1%) started 1-day before colitis induction and lasted for 5-days. Disease activity index, macroscopic scores, and serum C-reactive protein were evaluated. Colonic M1 markers and phosphorylated STAT3 levels were assessed using ELISA/RT-qPCR. PST (200ng/ml) treated-naïve peritoneal macrophages were exposed for 6 h to LPS (100ng/ml) to promote M1. M1 markers were quantified. In vitro chemotaxis activity of PST (200ng/ml) on naïve macrophages were assessed by transwell migration assay using MCP-1 (30ng/ml) as a chemoattractant. Patients with UC exhibited a 10-fold increase in colonic and serum levels of PST compared with healthy individuals. PTS also positively correlated with proinflammatory macrophages (M1) mediators and negatively with STAT3. Experimentally, colonic levels of PST elevated in Chga+/+ mice with DSS-induced colitis. Administration of PST worsened the severity of colitis associated with an increase of M1 macrophages cytokine and chemokines, and a decrease of STAT3 level in Chga+/+ and Chga-/- mice. In vitro, peritoneal M1 associated cytokines significantly increased in PST-conditioned Chga-/- M1 that linked to a reduction in STAT3 level. In undifferentiated macrophages, PST dramatically enhanced macrophages migration. The aggravation of intestinal inflammation exists only in the presence of PST, and its absence leads to a reduction of disease severity, a decrease of M1 activation and an increase in STAT3. Targeting PST may lead to a novel therapeutic strategy in IBD. CCC, CIHRResearch Manitoba, Canada
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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 | 0.001 |
| 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".