Inhibition of cytokine production and interference in IL‐2 receptor‐mediated Jak‐Stat signaling by the hydroxylamine metabolite of sulfamethoxazole
Bibliographic record
Abstract
ABSTRACT Sulfonamides, used for the treatment of opportunistic infections in immunocompromised patients, are associated with a high incidence of adverse drug events, including severe hypersensitivity reactions. Imbalances in the production and detoxification of reactive sulfonamide metabolites have been implicated in the pathogenesis of these life‐threatening reactions. The hydroxylamine metabolite of sulfamethoxazole (SMX‐HA) inhibits the proliferation of mitogen‐stimulated peripheral blood mononuclear cells (PBMCs) in vitro without reducing Interleukin 2 (IL‐2) expression. We investigated the effects of SMX‐HA on accessory cytokine expression and IL‐2 receptor (IL‐2R) mediated signal transduction. SMX‐HA did not reduce significantly mRNA production of proinflammatory [tumor necrosis factor α (TNF‐α) and IL‐lβ], Thl‐type (IFN‐γ), and Th2‐type cytokines (IL‐4 and IL‐10). Sublethal concentrations of SMX‐HA (25 μM) reduced significantly the production of TNF‐α, IL‐lβ, and IL4 protein without inhibiting the production of IFN‐γ. This finding suggests that exposure to SMX‐HA might direct a response towards a Th‐1 vs. a Th‐2 response. Immunoblot analysis of IL‐2R‐mediated Janus kinases and signal transduction activators of transcription (Jak‐Stat) signal transduction revealed diminished phosphorylation of Jak1 and Jak3 and inhibited downstream phosphorylation of Stat3, Stat5a, and IL‐2Rγ in phytohemagglutinin/rIL‐2 activated PBMCs treated with SMX‐HA. SMX‐HA did not inhibit Jak association with IL‐2Rγ or IL‐2Rβ. These data illustrated that sublethal concentrations of SMX‐HA interfere with IL‐2R‐mediated signal transduction, resulting in altered cytokine production and inhibition of lymphocyte proliferation.
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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 | 0.001 | 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) | 0.000 | 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".