Annexin 1: More than an anti-phospholipase protein

Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.
Inflammation Research (Impact Factor: 2.35). 05/2004; 53(4):125-32. DOI: 10.1007/s00011-003-1235-z
Source: PubMed


Annexin 1 (ANXA1) is the first characterized member of the annexin family of proteins able to bind (i.e. to annex) to cellular membranes in a calcium-dependent manner. ANXA1 may be induced by glucocorticoids in inflammatory cells and shares with these drugs many anti-inflammatory effects. Originally described as a phospholipase A2 (PLA2)-inhibitory protein, ANXA1 can affect many components of the inflammatory reaction besides the metabolism of arachidonic acid. Recent data have shown that ANXA1 may specifically target cytosolic PLA2 by both direct enzyme inhibition and suppression of cytokine-induced activation of the enzyme. ANXA1 inhibits the expression and/or activity of other inflammatory enzymes like inducible nitric oxide synthase (iNOS) in macrophages and inducible cyclooxygenase (COX-2) in activated microglia. The inhibition of iNOS expression may be caused by the stimulation of IL-10 release induced by ANXA1 in macrophages. Like glucocorticoids, ANXA1 exerts profound inhibitory effects on both neutrophil and monocyte migration in inflammation. Several mechanisms may contribute to the protein effect on cell migration, namely the activation of receptors like the formyl peptide receptor (FPR) and the lipoxin A4 receptor (ALXR), the shedding of L-selectin, the binding to alpha4beta1 integrin and carboxylated N-glycans. Furthermore, again mimicking the action of glucocorticoids, ANXA1 promotes inflammatory cell apoptosis associated with transient rise in intracellular calcium and caspase-3 activation. Finally, ANXA1 has been recently identified as one of the 'eat-me' signals on apoptotic cells to be recognised and ingested by phagocytes. Thus, ANXA1 may contribute to the anti-inflammatory signalling that allows safe post-apoptotic clearance of dead cells.

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    • "Calpactin and annexin II were shown here to be upregulated by approximately 37% and 23%, respectively by acute hyperglycemic conditions. Calpactin complexed to annexin II is known to interact with the C-terminus of cytosolic phospholipase A2 and inhibits cPLA2 activity thus reducing inflammatory responses from the release of arachidonic acid [28]. Upregulation of reticulocalbindin 3 is necessary for increased sequestration of Ca 2+ . "
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    • "During the initial steps of acute inflammation, AnxA1 limits the recruitment of leukocytes and the production of proinflammatory mediators [80]. During the resolution phase, AnxA1 acts by inducing the apoptosis of neutrophils and this effect is associated with increased expression of cleaved caspase-3 and BAX and decreased expression of pERK1/2, NF-κB, and MCL-1 [21, 81–83] and increasing efferocytosis by macrophages [83–85]. Interestingly, activation of FPR2 by AnxA1 and LXA4 skewed M1 macrophages to M2-like cells [86]. "
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    • "Annexin A1 (AnxA1), originally reported as a calcium and phospholipid binding protein induced by glucocorticoids, is an endogenous anti-inflammatory mediator. The antiinflammatory effects of AnxA1 have been documented in vivo and in vitro, and include inhibition of leukocyte recruitment, inhibition of pro-inflammatory cytokine expression, inhibition of phospholipase A2 activity and induction of apoptosis (Lim et al., 2007; Parente et al., 2004; Perretti et al., 2009). A role for AnxA1 in the regulation of inflammatory arthritis has been supported by several studies. "
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