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IL-4 induced non-canonical trained immunity in murine BMDMs

ABSTRACT: The canonical role IL-4 is to induce M2 macrophage polarization. Herein we report that in addition to its canonical role, IL-4 also induces non-canonical pro-inflammatory response via epigenetic memory. Although IL-4 stimulated macrophages do not produce classic proinflammatory cytokines such as IL-6 and IL-1b, they produce heightened proinflammatory cytokine upon LPS stimulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE184811 | GEO | 2022/12/31

REPOSITORIES: GEO

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Project description:Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression at the transcriptional level, leading to activation of autocrine and paracrine JAK/STAT signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent on the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two other factors: IKKÎ², a protein in the NF-kB signaling cascade, and p53. Activation of IL-6 by Notch required IKKÎ² function, but interestingly, did not engage canonical NF-ÎºB signaling, in contrast to IL-6 activation by inflammatory agents such as tumor necrosis factor, which requires canonical NF-ÎºB signaling. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, but restoring wildtype 53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced genome-wide transcriptomes from p53 wildtype and -mutated breast tumor cell lines differed extensively, and in a subset of genes upregulated by Notch in a p53-mutant cell line, upregulation was reduced by wildtype p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKÎ² in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output. 30 microarray samples consisting of MCF7 (ER+, wild-type p53, luminal type B breast cancer) and MDA-MB-231 (ER-, mutated p53, basal breast cancer) cells cultured on immobilized 1 Î¼g/ml JAGGED1-Fc or 1 Î¼g/ml DLL4-Fc or 1 Î¼g/ml Fc control with or without 5 Î¼M DAPT for 6 hours in 3 biological replicates.

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IL-4 induced non-canonical trained immunity in murine BMDMs

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