Adenosine A2A receptor signaling attenuates LPS-induced pro-inflammatory cytokine formation of mouse macrophages by inducing the expression of DUSP1

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Adenosine in the Thymus

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Anti-inflammatory Mechanisms Triggered by Apoptotic Cells during Their Clearance

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Anti-inflammatory Mechanisms Triggered by Apoptotic Cells during Their Clearance

In the human body, billions of cells die by apoptosis every day. The subsequent clearance of apoptotic cells by phagocytosis is normally efficient enough to prevent secondary necrosis and the consequent release of cell contents that would induce inflammation and trigger autoimmunity. In addition, apoptotic cells generally induce an anti-inflammatory response, thus removal of apoptotic cells is usually immunologically silent. Since the first discovery that uptake of apoptotic cells leads to transforming growth factor (TGF)-β and interleukin (IL)-10 release by engulfing macrophages, numerous anti-inflammatory mechanisms triggered by apoptotic cells have been discovered, including release of anti-inflammatory molecules from the apoptotic cells, triggering immediate anti-inflammatory signaling pathways by apoptotic cell surface molecules via phagocyte receptors, activating phagocyte nuclear receptors following uptake and inducing the production of anti-inflammatory soluble mediators by phagocytes that may act via paracrine or autocrine mechanisms to amplify and preserve the anti-inflammatory state. Here, we summarize our present knowledge about how these anti-inflammatory mechanisms operate during the clearance of apoptotic cells

Membrane array and multiplex bead analysis of tear cytokines in systemic sclerosis

Although serious ocular manifestations of systemicsclerosis (SSc) have been described, tear analysis ofpatients with SSc has not been performed in previousstudies. Our aim was to measure a wide panel of cytokinesand chemokines in tears of patients with SSc and to assessthe most significant molecules with a more sensitive andspecific method. Unstimulated tear samples were collectedfrom nine patients with SSc and 12 age- and gender-matchedhealthy controls. The relative levels of 102 differentcytokines were determined by a cytokine array, and thenabsolute levels of four key cytokines were determined by amagnetic bead assay. Array results revealed shifted cytokineprofile characterized by predominance of inflammatorymediators. Of the 102 analyzed molecules, nine weresignificantly increased in tears of patients with SSc. Basedon the multiplex bead results, C-reactive protein, interferon-c-inducible protein-10, and monocyte chemoattractant protein-1 levels were significantly higher in tears of patients with SSc. Our current data depict a group of inflammatory mediators, which play a significant role in ocular pathology of SSc; furthermore, they might function as excellent candidates for future therapeutic targets in SSc patients with ocular manifestations

Transglutaminase 2 null macrophages respond to lipopolysaccharide stimulation by elevated proinflammatory cytokine production due to an enhanced αvβ3 integrin-induced Src tyrosine kinase signaling

Transglutaminase 2 (TG2) is a protein crosslinking enzyme with several additional biochemical functions. Loss of TG2 in vivo results in impaired phagocytosis of apoptotic cells and altered proinflammatory cytokine production by macrophages engulfing apoptotic cells leading to autoimmunity. It has been proposed that TG2 acts as an integrin ß(3) coreceptor in the engulfment process, while altered proinflammatory cytokine production is related to the lack of latent TGFß activation by TG2 null macrophages. Here we report that TG2 null macrophages respond to lipopolysaccharide treatment by elevated IL-6 and TNFa production. Though TGFß has been proposed to act as a feed back regulator of proinflammatory cytokine production in LPS-stimulated macrophages, this phenomenon is not related to the lack of active TGFß production. Instead, in the absence of TG2 integrin ß(3) maintains an elevated basal Src family kinase activity in macrophages, which leads to enhanced phosphorylation and degradation of the I?Ba. Low basal levels of I?Ba explain the enhanced sensitivity of TG2 null macrophages to signals that regulate NF-?B. Our data suggest that TG2 null macrophages bear a proinflammatory phenotype, which might contribute to the enhanced susceptibility of these mice to develop autoimmunity and atherosclerosis

Loss of Transglutaminase 2 Sensitizes for DietInduced Obesity-Related Inflammation and Insulin Resistance due to Enhanced Macrophage c-Src Signaling

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