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1.
EMBO Mol Med ; 3(2): 102-14, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21254404

ABSTRACT

The immunosuppressive effects of apoptotic cells involve inhibition of pro-inflammatory cytokine release and establishment of an anti-inflammatory cytokine profile, thus limiting the degree of inflammation and promoting resolution. We report here that this is in part mediated by the release of the anti-inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor (FPR) family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2-26 significantly reduced IL-6 signalling and the release of TNF-α from endotoxin-challenged monocytes. Ac2-26 activated STAT3 in a JAK-dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2-26-mediated inhibition of IL-6 signalling. This identifies annexin A1 as part of the anti-inflammatory pattern of apoptotic cells and links the activation of FPRs to established signalling pathways triggering anti-inflammatory responses.


Subject(s)
Annexin A1/immunology , Apoptosis , Immune Tolerance , Monocytes/immunology , Receptors, Formyl Peptide/immunology , Signal Transduction , Annexin A1/metabolism , Interleukin-6/metabolism , Janus Kinases/metabolism , Neutrophils/immunology , Peptides/immunology , Peptides/metabolism , Receptors, Formyl Peptide/metabolism , STAT3 Transcription Factor/metabolism , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/metabolism , Tumor Necrosis Factor-alpha/metabolism
2.
J Leukoc Biol ; 82(6): 1592-604, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17855500

ABSTRACT

Annexin A1 is a glucocorticoid-regulated, anti-inflammatory protein, which plays an important role as an endogenous regulator of the inflammatory response. Many of these anti-inflammatory properties are retained in the N-terminal annexin A1 peptide Ac1-25, which is released from the full-length protein by a neutrophil elastase. To elucidate whether the anti-inflammatory activity of the bioactive peptide is solely a result of immediate post-translational effects, which include the shedding of L-selectin or also involve transcriptional changes affecting leukocyte function, we recorded global gene expression changes in human monocytes stimulated with exogenously applied Ac1-25. Applying stringent selection criteria, we show that approximately 100 genes are up-regulated, and approximately 230 are down-regulated by a factor of at least two in the Ac1-25-treated monocytes. It is important that the profiling reveals that Ac1-25 induces an anti-inflammatory phenotype by down-regulating proinflammatory and up-regulating anti-inflammatory mediators. These effects, elicited by exogenously applied Ac1-25, depend, to different extents, on ERK1/2 and p38 signaling pathways. This identifies the annexin A1 N-terminal peptide as a stimulus, eliciting not only short-term, post-translational effects in human monocytes but also transcriptional changes, defining a more anti-inflammatory profile.


Subject(s)
Annexin A1/pharmacology , Gene Expression Profiling , Gene Expression Regulation/drug effects , Inflammation/genetics , Monocytes/drug effects , Monocytes/metabolism , Transcription, Genetic/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Inflammation/enzymology , Interleukin 1 Receptor Antagonist Protein/metabolism , MAP Kinase Signaling System/drug effects , Monocytes/enzymology , Peptides/pharmacology , Receptors, CCR2/metabolism , Time Factors , p38 Mitogen-Activated Protein Kinases/metabolism
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