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GSE68968
Mus musculus
6 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Normal arteries contain a large population of tissue resident macrophages (M). Their origins, as well as the mechanisms that sustain them during homeostasis and disease, however, are poorly understood. Gene expression profiling, we show, identifies arterial M as a distinct population among tissue M. Ontologically, arterial M arise before birth, though CX3CR1-, Csf1r-, and Flt3-driven fate mapping approaches demonstrate M colonization occurs through successive contributions of yolk sac (YS) and conventional hematopoiesis. In adulthood, arterial M renewal is driven by local proliferation rather than monocyte recruitment from the blood. Proliferation sustains M not only during steady state conditions, but mediates their rebound after severe depletion following sepsis. Importantly, the return of arterial M to functional homeostasis after infection is rapid; repopulated M exhibit a transcriptional program similar to resting M and efficiently phagocytose bacteria. Collectively, our data provide a detailed framework for future studies of arterial M function in health and disease.
Publication Title
Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 17 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in responding to injury or infection as well as immune response, inflammation, and hematopoiesis. High levels of circulating IL-6 are observed in many tumor types and are associated with poor outcomes. We show that knockdown of IL-6 or IL-6 receptor (IL-6R) inhibits IL-6 signaling and cell viability. In contrast, over-expression of IL-6 enhances tumor growth in vitro and in vivo, thereby supporting the role of IL-6 in tumorigenesis. We developed a human monoclonal antibody against human IL-6 (MEDI5117) that bears Fc mutations (YTE) to extend its half-life. We tested this antibody in several cancer cell lines that secrete high levels of IL-6, soluble IL-6R, and express gp130. High constitutive pSTAT3 (phosphorylated signal transducer and activator of transcription 3) activation is seen in several of these cell lines, suggesting autocrine growth stimulation by IL-6. Treating these cell lines with MEDI5117 effectively blocked phosphorylation of STAT3 and inhibited IL-6-induced cell proliferation. In vivo, MEDI5117 suppressed the growth of multiple cancer xenograft models and specifically modulated IL-6 signaling and downstream gene expression. Combining MEDI5117 with chemotherapy or gefitinib demonstrated significantly enhanced anti-tumor activities in vivo. Taken together, our data suggest that IL-6 signaling contributes to tumor growth, thereby supporting the development of MEDI5117 as a therapy to treat solid tumors.
Publication Title
A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors.
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Specimen part
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