The roles of SH2-containing inositol 5'-phosphatase 1 (SHIP1) and signal transducer and activator of transcription 3 (STAT3) in interleukin-10 regulation of activated macrophages
Bibliographic record
Abstract
Inflammation is a protective mechanism against infection, but it must be appropriately regulated to prevent pathological consequences including inflammatory diseases. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that inhibits the activation of many immune cell types, including the macrophage, to prevent exaggerated immune responses. Understanding the signalling pathway downstream of IL-10 and IL-10 receptor (IL-10R) is essential in developing therapeutics to treat inflammatory diseases. Canonically, IL-10R signalling is described as solely depending on the activation of the transcription factor STAT3 and the expression of STAT3-response genes. However, our laboratory has previously shown that IL-10 also activates the inositol 5'-phosphatase SHIP1 to mediate its anti-inflammatory responses, such as inhibiting the expression of pro-inflammatory cytokines. Moreover, we have now found that IL-10 is able to inhibit expression of miRNA-155 (miR-155) in macrophages activated by the bacterial product lipopolysaccharide (LPS). This inhibition by IL-10 requires both STAT3 and SHIP1, and occurs at the maturation step, but not at the transcription step, of miR-155. Consistent with SHIP1’s involvement in IL-10 function, a previously described SHIP1 activator, AQX-MN100, mimics IL-10 and inhibits LPS-induced miR-155. Next, we investigated the roles of STAT3 and SHIP1 in IL-10 regulation of global gene expression in activated macrophages. Among the genes identified as IL-10 regulated, we have found different subsets of genes potentially to be SHIP1-regulated, STAT3-regulated, and SHIP1-STAT3 regulated. Considering the importance of SHIP1 activation in IL-10 function, SHIP1 activators provide an alternate way to control inflammation. We have previously shown that SHIP1 activators bind to SHIP1’s C2 domain and regulate SHIP1 enzymatic activity allosterically. Using x-ray crystallography, we obtained the crystal structure of SHIP1’s phosphatase and C2 domains, the minimal region necessary for allosteric activation by SHIP1 activators. Analysis of the crystal structure revealed differences between SHIP1 and related phosphatases. Biochemical and biophysical methods have been employed to identify amino acid residues potentially interacting with SHIP1 activators. Together, this work strengthens the model that STAT3 and SHIP1 work together to mediate the anti-inflammatory function of IL-10. We also described the structure of SHIP1, providing the first step in rational drug design to generate better small molecule SHIP1 activators.
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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) | 0.001 | 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".