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Acknowledgements Work from our laboratory was supported by grant AG21450 from the National Institutes of Health, USA. DAtABAsEs entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?db=gene cD28 | CDKN2A | FGFr2 | growth hormone | iGF1 | iL-6 | iL-7 | KGF FURtHER inFoRMAtion Kenneth Dorshkind’s homepage: http://faculty.uclaaccess. ucla.edu/institution/personnel?personnel_id=45615 Us census Bureau: http://www.cdc.gov/nchs/data/hus/ hus07.pdf#fig01 World Health Organization: http://www.who.int/en/ seNieUr Protocol: http://www.medizin.uni-tuebingen.de/ eucambis/home/senieur.html All lInks ArE AcTIvE In ThE onlInE pdf Inflammation is a primordial response that functions to protect the host against invasion by pathogens or exposure to xenobiotics. However, overly aggressive or prolonged inflammatory responses can be detrimental to the host. Therefore, higher organisms have evolved mechanisms to ensure that the inflammatory response is limited in time and space. Many endogenous anti- inflammatory and pro-resolving mediators function to counteract the properties of pro- inflammatory factors and to ensure a prompt resolution of inflammation. The concept that inflammation is resolved in a time- and space-specific manner is emerging, such that different outcomes can be produced accord- ing to the stage or site at which a given pathway or mediator becomes operative 1,2 . The action of anti-inflammatory and pro- resolving mediators and pathways on several components of the inflammatory response is crucial for restoring tissue structure and homeostasis. Elucidation of their effects on immune cells could lead to the identification of the molecular target (or targets) of a given mediator, thereby prompting innovative drug discovery for the treatment of chronic inflammatory conditions 2,3 . Glucocorticoids are the first class of endogenous anti-inflammatory mediators that have been successfully used for thera- peutic purposes; budesonide and beclo- methasone are widely used for the treatment of asthma, prednisolone is used for rheu- matoid arthritis and other autoimmune diseases, and mometasone and hydrocorti- sone are used for eczema and psoriasis. In healthy individuals, the circadian release of glucocorticoids (such as cortisol and corticosterone) from the adrenal glands facilitates the control of several homeostatic processes that are crucial for health. During inflammation, increased levels of cortisol dampen local and systemic inflammatory events, thereby favouring proper resolution of the inflammatory response 4,5 . These fundamental pathophysiological functions of glucocorticoids are achieved through many molecular mechanisms, which can be broadly divided into genomic mechanisms (involving transactivation or transrepres- sion of gene transcription) and non- genomic mechanisms (that are rapid and independent of de novo protein synthesis) (BOX 1). In this Opinion article, we focus on one downstream mediator of glucocorticoids, the 37 kDa protein annexin A1 (also known as lipocortin 1; encoded by ANXA1). We review the recent evidence indicating that glucocorticoids regulate the synthesis and function of annexin A1 (REFS 4,6), possibly through a combination of both genomic and non-genomic processes, depending on the cell type and the time of induction. In addition, we describe the emerging data showing that glucocorticoids can differentially affect the annexin A1 path- way in cells of the innate and adaptive immune system, in which this pathway can have opposing effects. We propose that the annexin A1 pathway is an important mediator of the anti-inflammatory effects of glucocorticoids. Effects in innate immunity Annexin A1 is a member of a superfamily of annexin proteins that bind acidic phospho- lipids with high affinity in the presence of Ca 2+ (REF. 7). There are 13 mammalian annexin proteins, each of which has specific biological functions. Similarly to other annexin proteins, annexin A1 is expressed in resting cells and binds to acidic phospho- lipids in the presence of Ca 2+ ; original studies of annexin A1 therefore focused on its role in granule fusion and exocytosis, in which it was shown to promote the fusion of vesicle membranes with plasma membranes in reconstituted systems 7 . The actions of annexin A1. In resting con- ditions, human and mouse neutrophils, monocytes and macrophages constitutively contain high levels of annexin A1 in their cytoplasm 8–10 . Following cell activation (for example, by neutrophil adhesion to endothelial-cell monolayers), annexin A1 is promptly mobilized to the cell surface and secreted 11 . The molecular mechanisms that are responsible for this rapid secretion are cell specific. In macrophages, the oPinion Annexin A1 and glucocorticoids as effectors of the resolution of inflammation Mauro Perretti and Fulvio D’Acquisto Abstract | Glucocorticoids are widely used for the management of inflammatory diseases. Their clinical application stems from our understanding of the inhibitory effect of the corticosteroid hormone cortisol on several components of the immune system. endogenous and exogenous glucocorticoids mediate their multiple anti-inflammatory effects through many effector molecules. in this Opinion article, we focus on the role of one such effector molecule, annexin A1, and summarize the recent studies that provide insight into its molecular and pharmacological functions in immune responses. in addition, we propose a model in which glucocorticoids regulate the expression and function of annexin A1 in opposing ways in innate and adaptive immune cells to mediate the resolution of inflammation. PersPectives 62 | JANUARY 2009 | VOLUME 9 www.nature.com/reviews/immunol © 2009 Macmillan Publishers Limited. All rights reserved