Loss of TRIM24 promotes IL-10 expression via CBP/p300-dependent IFNß1 transcription during macrophage activation.

BACKGROUND: As an anti-inflammatory cytokine, interleukin 10 (IL-10) plays a vital role in preventing inflammatory and autoimmune pathologies while also maintaining immune homeostasis. IL-10 production in macrophages is tightly regulated by multiple pathways. TRIM24, a member of the Transcriptional Intermediary Factor 1 (TIF1) family, contributes to antiviral immunity and macrophage M2 polarization. However, the role of TRIM24 in regulating IL-10 expression and its involvement in endotoxic shock remains unclear. METHODS: In vitro, bone marrow derived macrophages cultured with GM-CSF or M-CSF were stimulated with LPS (100ng/ml). Murine models of endotoxic shock were established by challenging the mice with different dose of LPS (i.p). RTPCR, RNA sequencing, ELISA and hematoxylin and eosin staining were performed to elucidate the role and mechanisms of TRIM24 in endotoxic shock. RESULTS: The expression of TRIM24 is downregulated in LPS-stimulated bone marrow-derived macrophages (BMDMs). Loss of TRIM24 boosted IL-10 expression during the late stage of LPS-stimulation in macrophages. RNA-seq analysis revealed the upregulation of IFNß1, an upstream regulator of IL-10, in TRIM24 knockout macrophages. Treatment with C646, a CBP/p300 inhibitor, diminished the difference in both IFNß1 and IL-10 expression between TRIM24 knockout and control macrophages. Loss of TRIM24 provided protection against LPS-induced endotoxic shock in mice. CONCLUSION: Our results demonstrated that inhibiting TRIM24 promoted the expression of IFNß1 and IL-10 during macrophage activation, therefore protecting mice from endotoxic shock. This study offers novel insights into the regulatory role of TRIM24 in IL-10 expression, making it a potentially attractive therapeutic target for inflammatory diseases.

IFNß1 secreted by breast cancer cells undergoing chemotherapy reprograms stromal fibroblasts to support tumour growth after treatment.

Chemotherapy (CTX) remains the standard of care for most aggressive tumours, including breast cancer (BC). In BC chemotherapeutic regimens, the maximum tolerated dose of cytotoxic drugs is administered at regular intervals, and cancer cells can re-grow or adapt during the resting periods between cycles. The impact of the tumour microenvironment on the fate of cancer cells after CTX remains poorly understood. Here, we show that paracrine signalling from CTX-treated cancer cells to stromal fibroblasts can drive cancer cell recovery after cytotoxic drug withdrawal. Interferon ß1 (IFNß1) secreted by cancer cells following treatment with high doses of CTX instigates the acquisition of an anti-viral state in stromal fibroblasts. This state is associated with an expression pattern here referred to as interferon signature (IFNS), which encompasses several interferon-stimulated genes (ISGs), including numerous pro-inflammatory cytokine genes. This crosstalk is an important driver of the expansion of BC cells after CTX, and IFNß1 blockade in tumour cells abrogated their fibroblast-dependent recovery potential. Analysis of human breast carcinomas supported a link between CTX-induced IFNS in tumour stroma and poor response to CTX treatment. First, IFNß1 expression in human breast carcinomas was found to inversely correlate with recurrence free survival (RFS). Second, using laser capture microdissection data sets, we show a higher expression of IFNS in the stromal tumour compartment compared to the epithelial one and this signature was found to be more prominent in more aggressive subtypes of BC (basal-like), pointing to a pro-tumorigenic role of this signature. Moreover, IFNS was associated with higher recurrence rates and a worse outcome in BC patients. Our study unravels a novel form of paracrine communication between cancer cells and fibroblasts that ultimately results in CTX resistance. Targeting this axis has the potential to improve CTX outcomes in patients with BC.

A Long Non-coding RNA IVRPIE Promotes Host Antiviral Immune Responses Through Regulating Interferon ß1 and ISG Expression.

Accumulating studies have shown that long non-coding RNAs (lncRNAs) modulate multiple biological processes, including immune response. However, the underlying mechanisms of lncRNAs regulating host antiviral immune response are not well elucidated. In this study, we report that analysis of the existing dataset transcriptome of blood immune cells of patients with influenza A virus (IAV) infection and after recovery (GSE108807) identified a novel lncRNA, termed as IVRPIE (Inhibiting IAV Replication by Promoting IFN and ISGs Expression), was involved in antiviral innate immunity. In vitro studies showed that IVRPIE was significantly upregulated in A549 cells after IAV infection. Gain-and-loss of function experiments displayed that enforced IVRPIE expression significantly inhibited IAV replication in A549 cells. Conversely, silencing IVRPIE promoted IAV replication. Furthermore, IVRPIE positively regulates the transcription of interferon ß1 and several critical interferon-stimulated genes (ISGs), including IRF1, IFIT1, IFIT3, Mx1, ISG15, and IFI44L, by affecting histone modification of these genes. In addition, hnRNP U was identified as an interaction partner for IVRPIE. Taken together, our findings suggested that a novel lncRNA IVRPIE is a critical regulator of host antiviral response.