Bibliographic record
Abstract
Complement is an innate pro-inflammatory host defense mechanism which bridges the innate and adaptive immune system yet the contribution of complement activation to the inflammatory bowel diseases is poorly understood. With the emerging understanding that gut microbes are part of the etiology of IBD, combined with evidence that complement is present in the colonic lumen, our purpose became to determine whether epithelial cells detect and respond to the anaphylatoxins, in particular the split component C5a. Using model human colonic cell lines T84 and Caco-2, we assayed the cells for mRNA and protein for the molecules of interest by RT/PCR and Western blotting, respectively. We first confirmed that the cell lines made multiple complement components, supporting others' evidence that complement is in the lumen. We then assayed for the two C5a receptors, C5aR and C5L2 (a decoy form) and both were detected. We used confocal microscopy to localize the C5a receptors and found both proteins are limited to the apical surface of cells growing polarized on Transwell filters. Understanding that complement activation is inflammatory, we speculated that C5a would stimulate further inflammatory activities and thus assessed whether the cell lines made chemokines after exposure to C5a. Despite possessing the C5L2, C5a treated T84 but not Caco-2 cells increased mRNA levels for CXCL8 and CXCL11 but failed to secrete increased amounts of protein compared to naïve cells. The C5aR is a seven-membrane spanning G-protein linked receptor primarily signaling through increases in cAMP yet increases in chemokine gene transcription and secretion are often associated with activation of the MAP kinases. Thus we assessed the state of MAP kinase activation following exposure of the cells to C5a and found ERK became activated in both cell lines. Pharmacologic inhibition of ERK activity in C5a treated T84 cells blocked the CXCL8 mRNA increase. In conclusion a relatively weak ERK activation accounts for the partial CXCL8 upregulation by C5a, and the cells likely require a second signal for protein secretion. The finding of the C5aR on the apical membrane of colonic epithelial cells indicates there is a direct effect of complement activation in the lumen to recruit the epithelium into expanding the inflammatory response. Such a process could be linked to the trigger for inflammatory diseases in the gut. This project is funded by a grant from the Natural Sciences and Engineering Research Council of Canada.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.005 | 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 teacher head, 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".