Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling.
Bottom Line: 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.
Affiliation: Centre for Molecular Biology of Inflammation, and Interdisciplinary Clinical Research Centre, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany.Show MeSH
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Mentions: Activated STAT3 molecules form a homodimer which translocates into the nucleus, where it recognizes specific DNA elements and activates transcription. To assess STAT3 activation, nuclear translocation and DNA binding, we treated monocytes with apoptotic cell culture supernatant, prepared cytosolic and nuclear extracts and probed for tyrosine-phosphorylated STAT3 by Western blotting. As shown in Fig 2A, increased amounts of tyrosine-phosphorylated STAT3 were detected in the nuclear, but not in the cytosolic fraction upon 60–90 min addition of apoptotic cell culture supernatant. Furthermore, electrophoretic mobility shift assay (EMSA) analysis revealed that nuclear extracts from monocytes treated for 60 min with apoptotic cell culture supernatant contained more STAT3 bound to its cognate DNA probe than extracts from untreated control cells (Fig 2B, lanes 1 and 3). The observed STAT3 binding was highly specific, since binding to the DNA was completely inhibited in the presence of a 100-fold molar excess of unlabelled probe (Fig 2B, lanes 2 and 4).
Affiliation: Centre for Molecular Biology of Inflammation, and Interdisciplinary Clinical Research Centre, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany.