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 determine directly whether annexin A1 is involved in the process of anti-inflammatory activation, we incubated monocytes for various periods of time with the Ac2-26 peptidomimetic and monitored STAT3 activation. The annexin A1 N-terminal peptide transiently activated STAT3 phosphorylation in a dose- and time-dependent manner. Phosphorylation of STAT3 tyrosine 705 was robustly detected upon 60 min of Ac2-26 stimulation and returned to basal levels at later time points (Fig 4A), thus again mirroring the effect of total apoptotic PMN supernatants. No evidence for activation of STATs 1, 2 or 5 was found in the samples (not shown). To rule out that the observed STAT3 activation was due to a contamination with bacterial endotoxins (Benkhart et al, 2000; Carl et al, 2004), activation with either LPS or Ac2-26 was carried out in the presence of the LPS inhibitor polymyxin B. As shown in Fig 4B, polymyxin B completely inhibited the LPS-induced STAT3 tyrosine phosphorylation, whereas STAT3 activation by Ac2-26 was unaffected, confirming that activation by the annexin A1 peptide was specific.
Affiliation: Centre for Molecular Biology of Inflammation, and Interdisciplinary Clinical Research Centre, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany.