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: To elucidate the effect of Ac2-26-induced STAT3 activation on the nuclear translocation of activated STAT3, we prepared cytoplasmic and nuclear extracts from annexin-treated monocytes and subjected them to immunoblotting with the phospho-STAT3-specific antibody. As shown in Fig 6A, pY-STAT3 was found in the nuclear fraction in response to Ac2-26. We next investigated whether Ac2-26-induced tyrosine phosphorylation of STAT3 correlated with STAT3 DNA binding activity. Therefore, monocytes were stimulated with Ac2-26 for 60 min, and the DNA binding activity of STAT3 was determined by EMSA. Whereas unstimulated cells showed relatively few STAT3/DNA complexes (Fig 6B, lane 1), STAT3 DNA-binding was readily observed in Ac2-26-treated monocytes (Fig 6B, lane 3). Collectively, these data indicate that Ac2-26 induces STAT3 phosphorylation, nuclear translocation and DNA binding via agonistic activation of the FPRs.
Affiliation: Centre for Molecular Biology of Inflammation, and Interdisciplinary Clinical Research Centre, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany.