Annexin-1 Regulates Macrophage IL-6 and TNF via Glucocorticoid-Induced Leucine Zipper

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 183(2):1435-45. DOI: 10.4049/jimmunol.0804000
Source: PubMed


Annexin-1 (ANXA1) is a mediator of the anti-inflammatory actions of endogenous and exogenous glucocorticoids (GC). The mechanism of ANXA1 effects on cytokine production in macrophages is unknown and is here investigated in vivo and in vitro. In response to LPS administration, ANXA1(-/-) mice exhibited significantly increased serum IL-6 and TNF compared with wild-type (WT) controls. Similarly, LPS-induced IL-6 and TNF were significantly greater in ANXA1(-/-) than in WT peritoneal macrophages in vitro. In addition, deficiency of ANXA1 was associated with impairment of the inhibitory effects of dexamethasone (DEX) on LPS-induced IL-6 and TNF in macrophages. Increased LPS-induced cytokine expression in the absence of ANXA1 was accompanied by significantly increased LPS-induced activation of ERK and JNK MAPK and was abrogated by inhibition of either of these pathways. No differences in GC effects on MAPK or MAPK phosphatase 1 were observed in ANXA1(-/-) cells. In contrast, GC-induced expression of the regulatory protein GILZ was significantly reduced in ANXA1(-/-) cells by silencing of ANXA1 in WT cells and in macrophages of ANXA1(-/-) mice in vivo. GC-induced GILZ expression and GC inhibition of NF-kappaB activation were restored by expression of ANXA1 in ANXA1(-/-) cells, and GILZ overexpression in ANXA1(-/-) macrophages reduced ERK MAPK phosphorylation and restored sensitivity of cytokine expression and NF-kappaB activation to GC. These data confirm ANXA1 as a key inhibitor of macrophage cytokine expression and identify GILZ as a previously unrecognized mechanism of the anti-inflammatory effects of ANXA1.

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Available from: Daniel Aeberli, Oct 08, 2015
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    • "In vitro, steroid-mediated clearance of apoptotic cells by monocyte-derived macrophages requires ANX-A1 and FPR2 (Maderna et al., 2005). Deficiency of ANX-A1 in murine macrophages and fibroblasts also impairs dexamethasone resolution of inflammation, including attenuation of its ability to blunt the upregulation of pro-inflammatory cytokines (Yang et al., 2006, 2009). Similar effects are observed in human lung fibroblasts in which endogenous ANX-A1 has been silenced (Jia et al., 2013). "
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    ABSTRACT: Myocardial infarction (MI) and its resultant heart failure remains a major cause of death in the world. The current treatments for patients with MI are revascularization with thrombolytic agents or interventional procedures. These treatments have focused on restoring blood flow to the ischemic tissue to prevent tissue necrosis and preserve organ function. The restoration of blood flow after a period of ischemia, however, may elicit further myocardial damage, called reperfusion injury. Pharmacological interventions, such as antioxidant and Ca(2+) channel blockers, have shown premises in experimental settings; however, clinical studies have shown limited success. Thus, there is a need for the development of novel therapies to treat reperfusion injury. The therapeutic potential of glucocorticoid-regulated anti-inflammatory mediator annexin-A1 (ANX-A1) has recently been recognized in a range of systemic inflammatory disorders. ANX-A1 binds to and activates the family of formyl peptide receptors (G protein-coupled receptor family) to inhibit neutrophil activation, migration and infiltration. Until recently, studies on the cardioprotective actions of ANX-A1 and its peptide mimetics (Ac2-26, CGEN-855A) have largely focused on its anti-inflammatory effects as a mechanism of preserving myocardial viability following I-R injury. Our laboratory provided the first evidence of the direct protective action of ANX-A1 on myocardium, independent of inflammatory cells in vitro. We now review the potential for ANX-A1 based therapeutics to be seen as a "triple shield" therapy against myocardial I-R injury, limiting neutrophil infiltration and preserving both cardiomyocyte viability and contractile function. This novel therapy may thus represent a valuable clinical approach to improve outcome after MI. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.012 · 9.72 Impact Factor
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    • "Mechanistic studies in THP-1 cells, a human monocyte cell line, show that GILZ directly interacts with the NF-κB p65 subunit and suppresses transcriptional activity, resulting in reduced expression of macrophage activation markers CD80, CD86, and TLR2, and chemoknies CCL5 and CCL3 (Berrebi et al., 2003). Moreover, another GC induced anti-inflammatory protein, AnxA1, requires GILZ to mediate inhibitory effects of GC in murine macrophage (Yang et al., 2009). In keeping with these findings, GILZ expression is inhibited in macrophages from patients with Crohn's disease, tuberculosis and alcoholic hepatitis (AH), typical inflammatory diseases associated with macrophage activation (Berrebi et al., 2003; Hamdi et al., 2007a). "
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    ABSTRACT: Glucocorticoids (GC) are the most commonly prescribed medications for patients with inflammatory diseases, despite their well-known adverse metabolic effects. Previously, it was understood that the anti-inflammatory effects of the GC/GC receptor (GR) complex were mediated via transrepression, whilst the adverse metabolic effects were mediated via transactivation. It has recently become clear that this "divergent actions" paradigm of GC actions is likely insufficient. It has been reported that the GC/GR-mediated transactivation also contributes to the anti-inflammatory actions of GC, via up-regulation of key anti-inflammatory proteins. One of these is glucocorticoid-induced leucine zipper (GILZ), which inhibits inflammatory responses in a number of important immune cell lineages in vitro, as well as in animal models of inflammatory diseases in vivo. This review aims to compare the GILZ and GC effects on specific cell lineages and animal models of inflammatory diseases. The fact that the actions of GILZ permit a GILZ-based gene therapy to lack GC-like adverse effects presents the potential for development of new strategies to treat patients with inflammatory diseases.
    Frontiers in Pharmacology 07/2014; 5:169. DOI:10.3389/fphar.2014.00169 · 3.80 Impact Factor
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    • "The effect of Cpd43 (1, 10 and 30 μM) on transcriptional activity of NFATc1 and NF-κB was examined in the presence or absence of LPS (10 ng/ml) or RANKL 100 ng/ml) for 6 (NF-κB) or 24 hours (NFAT). Luciferase activity was measured as previously described (Yang et al., 2009). "
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    ABSTRACT: Background and purpose: Annexin A1 (AnxA1) is an endogenous anti-inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast-like synoviocytes (FLS). Experimental approach: Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type (WT) or AnxA1(-/-) mice and clinical and histopathological manifestations measured 8-11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg(-1) i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL-induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages. Key results: Treatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF-α and osteoclast-associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 increased this release. Conclusions and implications: The FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA.
    British Journal of Pharmacology 05/2014; 171(17). DOI:10.1111/bph.12768 · 4.84 Impact Factor
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