Project description:The act of surgery strongly stimulated breast cancer cell growth in mice. Local irradiation of wounded breast efficiently prevented wounded-induced breast cancer cell growth. These modifications were linked to miR modulation both in human specimens and in the mouse model, in vivo. The most significantly IORT-induced miR was miR-223. miR-223 expression controlled EGF production and, eventually, cancer cell proliferation and survival.
Project description:Nitidine Chloride(NC) were found to enhance IL-10 production in LPS-stimulated Bone-marrow dendritic cells(BMDCs ) ,while at the same time inhibit pro-inflammatory cytokines production, such as TNF- α and IL-6. BMDCs were treated with NC or vehicle following LPS stimulation to find out the influence of NC on BMDCs that regulate cytokines expression. This study indicated that NC regulate numerous gene expression, thus influence IL-10 and pro-inflammatory cytokines production in LPS-treated BMDCs.
Project description:The ability of dying cells to activate antigen presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here we show that engulfed cells only containing cytosolic dsDNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs, via extrinsic STING-signaling. HEK293 cells containing double strand DNA robustly induced the production of cytokines in macrophages that was dependent on extrinsic STING signaling within the macrophage.
Project description:Th2 cells regulate helminth infections, allergic disorders, tumor immunity and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2-signaling molecules. While steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterised. We demonstrate production of the steroid pregnenolone by Th2 cells in vitro, and in vivo in a helminth infection model. To identify gene-expression identify of these steroidogenic-Th2 cells, we performed single-cell RNA-sequencing.
Project description:The Kaposiâs Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposiâs Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies. HUVEC cells were infected by KSHV or transduced by a CD147 recombinant adenoviral vector and the gene expression signature was compared to respective controls
Project description:COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the deaths in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive and there is no existing model where the disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune response, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, which might reflect the heterogeneity of human populations. In particular, two cytokines (IL-8 and IP-10) are highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination reveals focal cytopathic effects late in the infection, which are largely limited to type II alveolar cells. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoherringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.
Project description:The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1- population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant®), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection.
Project description:In Healthy State, we demonstrated the controlled expression of sphingolipids and the controlled IL-6,IL-17,IL-23 cytokines signalling via SOCS3 mediated regulation.
Project description:This data was performed as part of Revu et al, "Human IL-17A protein expression is controlled through a PIP5K1a-dependent ARS2 checkpoint". IL-17 secreted by TH17 cells is beneficial for microbial control, but causes inflammation and pathological tissue remodeling in autoimmunity. Hence TH17 differentiation and IL-17 production must be tightly regulated, but to date this has been defined only in terms of transcriptional control. Phosphatidyinositols are second messengers activated during T cell activation that transduce signals from the TCR and costimulatory receptors at the cell membrane. Here we show phosphatidylinositol(4,5)bisphosphate (PIP2) was unexpectedly enriched in the nucleus of human TH17 cells, dependent on the kinase PIP5K1, and that blockade of PIP5K1 impaired IL-17A production. In contrast, nuclear PIP2 enrichment was not observed in Th1 or Th2 cells and these subsets did not require PIP5K1 for cytokine production. In multiple sclerosis patient T cells, IL-17 production elicited by myelin basic protein could be inhibited by PIP5K1 blockade. Surprisingly, PIP5K1 blockade did not alter IL17A mRNA levels or stability in TH17 cells. Instead, analysis of PIP5K1-interacting proteins revealed that PIP5K1 targets ARS2, a nuclear cap binding complex scaffold protein, to facilitate ARS2 binding to IL17A mRNA and subsequent IL-17 protein expression, uncovering a new mechanism for regulating IL-17A protein production and suggesting a novel mechanism of translation control of cytokines.