Osteolysis of bone following total hip replacements is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone-resorption-inducing cytokine, interleukin 1β (IL-1β). NALP3, a NOD-like receptor protein located in the cytosol of macrophages, has been shown to signal the cleavage of pro-IL-1β into its mature, secreted form, IL-1β. Here we show that titanium particles stimulate the NALP3 inflammasome. We demonstrate that titanium induces IL-1β secretion from macrophages and this response is dependent on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase-1. We also show that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response is dependent on the expression of the IL-1 receptor and IL-1α/β. Moreover, administration of the IL-1 receptor antagonist (IL-1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle-induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL-1β secretion and IL-1-associated signaling, including neutrophil recruitment. Efficacy of IL-1Ra treatment introduces the potential for antagonist based-therapies for implant osteolysis.
We evaluated candidate genes in the cold sore susceptibility region using fine mapping with 45 SNP markers. 2 complementary techniques identified C21orf91 as a gene of interest for susceptibility to HSL. We propose that C21orf91 be designated the Cold Sore Susceptibility Gene-1 (CSSG1).
Antibody-mediated intracellular delivery of therapeutic agents has been considered for treatment of a variety of diseases. These approaches involve targeting cell-surface receptor proteins expressed by tumors or viral proteins expressed on infected cells. We examined the intracellular trafficking of a viral cell-surface-expressed protein, rabies G, with or without binding a specific antibody, ARG1. We found that antibody binding shifts the native intracellular trafficking pathway of rabies G in an Fc-independent manner. Kinetic studies indicate that the ARG1/rabies G complex progressively co-localized with clathrin, early endosomes, late endosomes, and lysosomes after addition to cells. This pathway was different from that taken by rabies G without addition of antibody, which localized with recycling endosomes. Findings were recapitulated using a cellular receptor with a well-defined endogenous recycling pathway. We conclude that antibody binding to cell-surface proteins induces redirection of intracellular trafficking of unbound or ligand bound receptors to a specific degradation pathway. These findings have broad implications for future developments of antibody-based therapeutics.
Osteolysis of bone following total hip replacements is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone-resorption-inducing cytokine, interleukin 1β (IL-1β). NALP3, a NOD-like receptor protein located in the cytosol of macrophages, has been shown to signal the cleavage of pro-IL-1β into its mature, secreted form, IL-1β. Here we show that titanium particles stimulate the NALP3 inflammasome. We demonstrate that titanium induces IL-1β secretion from macrophages and this response is dependent on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase-1. We also show that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response is dependent on the expression of the IL-1 receptor and IL-1α/β. Moreover, administration of the IL-1 receptor antagonist (IL-1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particleinduced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL-1β secretion and IL-1-associated signaling, including neutrophil recruitment. Efficacy of IL-1Ra treatment introduces the potential for antagonist based-therapies for implant osteolysis.
Current glioma therapy relies on induction of cytotoxicity after removal of the bulk tumor through the combination of surgery, radiation and temozolomide (TMZ); however, these therapies do not result in a long-term cure. Our lab previously demonstrated that some glioma cells undergo a transient cell cycle arrest in response to chemotherapy. Treatment with TMZ decreases sphere formation; however, after a short recovery period, a small number of cells resume sphere formation and self-renewal, measured by secondary sphere formation. Blocking the Notch pathway in neurosphere cultures with gamma-secretase inhibitors (GSIs) after TMZ treatment targeted the cells capable of recovery. TMZ + GSI treated cells do not recover and are no longer capable of self-renewal. TMZ + GSI synergy is dependent on the sequence of the drug treatments. Recovery was inhibited when GSI was administered 24 hrs after TMZ treatment. TMZ + GSI treatment also decreases tumorigenicity. When glioma cell lines were treated in vitro and implanted in immunodeficient mice, TMZ + GSI treatment extended latency and greatly increased survival. In addition, in vivo TMZ + GSI treatment completely blocked tumor progression and resulted in the loss of a palpable tumor in 50% of mice, while none of the TMZ-only treated mice survived. TMZ + GSI treated cultures and xenografts display a senescent phenotype. We observed an increase in the number of cells expressing senescence-associated beta-galactosidase and a decrease in Ki67 positive cells. Gene expression was also analyzed after drug treatments to confirm the induction of senescence. p21 is upregulated in cells that have undergone either a transient cell cycle arrest or senescence. We found that upregulation of p21 occurred initially in both TMZ-only and TMZ + GSI treatments, but only remained upregulated in the TMZ + GSI samples. This demonstrates that the addition of GSIs shifts TMZ-treated cells from a transient arrested state to a permanent senescent state. New therapy combinations, such as TMZ + GSI, are arising in a promising new field of cytostatic therapy and therapy-induced senescence (TIS). A key feature of TIS is the secretory profile of senescent cells. It was previously demonstrated that senescent tumor cells secrete inflammatory cytokines and activate the innate immune system for tumor clearance. We found that TMZ + GSI treatment resulted in upregulation of secreted IL-6 and IL-8 cytokines. We are currently the effect of senescent glioma cells on the innate immune system and tumor clearance. Overall, this data demonstrates the importance of the Notch pathway in chemoprotection and maintenance of TMZ-treated gliomas. The addition of GSIs to current treatments is promising target-directed therapy to decrease the rate of brain tumor recurrence inducing senescence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 963. doi:10.1158/1538-7445.AM2011-963
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