Browsing by Subject "Mice, Knockout"

Now showing 1 - 4 of 4
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    Influence of Tumour Necrosis Factor Alpha on the Outcome of Ischaemic Postconditioning in the Presence of Obesity and Diabetes
    (2012) Lacerda, Lydia; Opie, Lionel H; Lecour, Sandrine
    Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.
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    Open Access
    Prominent role for T cell-derived Tumour Necrosis Factor for sustained control of Mycobacterium tuberculosis infection
    (2013) Allie, Nasiema; Grivennikov, Sergei I; Keeton, Roanne; Hsu, Nai-Jen; Bourigault, Marie-Laure; Court, Nathalie; Fremond, Cecile; Yeremeev, Vladimir; Shebzukhov, Yuriy; Ryffel, Bernhard; Nedospasov, Sergei A; Quesniaux, Valérie F J; Jacobs, Muazzam
    Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF-producing CD4+ and CD8+ T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection.
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    Regulation of Cytosolic Phospholipase A 2 Activation and Cyclooxygenase 2 Expression in Macrophages by the β-Glucan Receptor
    (2006) Suram, Saritha; Brown, Gordon D; Ghosh, Moumita; Gordon, Siamon; Loper, Robyn; Taylor, Philip R; Akira, Shizuo; Uematsu, Satoshi; Williams, David L; Leslie, Christina C
    Phagocytosis of non-opsonized microorganisms by macrophages initiates innate immune responses for host defense against infection. Cytosolic phospholipase A(2) is activated during phagocytosis, releasing arachidonic acid for production of eicosanoids, which initiate acute inflammation. Our objective was to identify pattern recognition receptors that stimulate arachidonic acid release and cyclooxygenase 2 (COX2) expression in macrophages by pathogenic yeast and yeast cell walls. Zymosan- and Candida albicans-stimulated arachidonic acid release from resident mouse peritoneal macrophages was blocked by soluble glucan phosphate. In RAW264.7 cells arachidonic acid release, COX2 expression, and prostaglandin production were enhanced by overexpressing the beta-glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1, 3)-beta-D-glucan stimulated arachidonic acid release and COX2 expression, which were augmented in a Toll-like receptor 2 (TLR2)-dependent manner by macrophage-activating lipopeptide-2. However, arachidonic acid release and leukotriene C(4) production stimulated by zymosan and C. albicans were TLR2-independent, whereas COX2 expression and prostaglandin production were partially blunted in TLR2(-/-) macrophages. Inhibition of Syk tyrosine kinase blocked arachidonic acid release and COX2 expression in response to zymosan, C. albicans, and particulate (1, 3)-beta-D-glucan. The results suggest that cytosolic phospholipase A(2) activation triggered by the beta-glucan component of yeast is dependent on the immunoreceptor tyrosine-based activation motif-like domain of dectin-1 and activation of Syk kinase, whereas both TLR2 and Syk kinase regulate COX2 expression.
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    The protective role of DOT1L in UV-induced melanomagenesis
    (2018) Yin, Chengqian; Zhang, Jie; Wei, Wenyi; Wei, Zhi; Pan, Jingxuan; Wang, Yongjun; Xuan, Zhenyu; Hess, Jay; Hayward, Nicholas K; Goding, Colin R; Chen, Xiang; Zhou, Jun; Cui, Rutao
    The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.