IL-36/IL-36R signaling promotes CD4+ T cell-dependent colitis via pro-inflammatory cytokine production
Bibliographic record
Abstract
Background Inflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States. Several important factors are implicated in the pathogenesis of IBD, one factor being dysregulation of the immune system. This dysregulation results in the accumulation and stimulation of innate and adaptive immune cells, and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36γ, which is overexpressed in human IBD and experimental models of colitis. In this study, we explored the role of IL-36γ in promoting CD4 + T cell activation and cytokine secretion. Methods Spleens and lymph nodes were collected from wild-type and IFNγ -/- mice and were processed into cell suspensions to isolate naïve CD4 + T cells. Naïve CD4 + T cells were stimulated with IL-36 cytokines. IFNγ and TNFα were evaluated by ELISA using cell culture supernatants, and cell culture pellets were used to isolate RNA for qPCR. Naïve CD4 + T cells previously stimulated in the presence or absence of IL-36γ, from wild type (WT) or IFNγ-/- mice were transferred to Rag-/- mice to induce colitis. Fecal pellets were collected from mice during disease to analyze lipocalin (LCN2) levels from fecal supernatants. After euthanasia, colons, spleens, and mesenteric lymph nodes were harvested and processed into cell suspensions for intracellular cytokine staining. Results Our results demonstrate that IL-36γ stimulation of naive CD4 + T cells significantly induced IFNγ expression in vitro and was associated with augmented intestinal inflammation in vivo using the T cell transfer model of colitis. Using IFNγ -/- naive CD4 + T cells, we observed a dramatic decrease in the ability of these cells to produce TNFα. Moreover, the transfer of these cells to Rag -/- mice did not cause robust colitis. Conclusion These data not only suggest that IL-36γ is a regulator of a pro-inflammatory cytokine network involving IFNγ and TNFα but also highlights the importance of targeting IL-36γ and IFNγ as therapeutic approaches. Our studies have broad implications in relation to targeting specific cytokines in human IBD.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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 | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".