A potential role for annexin 1 as a physiologic mediator of glucocorticoid-induced L-selectin shedding from myeloid cells.
Glucocorticoids can dampen inflammatory responses by inhibiting neutrophil recruitment to tissue sites. The detailed mechanism by which glucocorticoids exert this affect on neutrophils is unknown. L-selectin is a leukocyte cell surface receptor that is implicated in several steps of neutrophil recruitment. Recently, several studies have shown that systemic treatment of animals and humans with glucocorticoids induces decreased L-selectin expression on neutrophils, suggesting one mechanism by which inflammation may be negatively regulated. However, when neutrophils are treated in vitro with glucocorticoids, no effect on L-selectin expression is observed. Thus, the existence of an additional mediator is plausible. In this study, we investigate whether annexin 1 (ANX1), a recognized second messenger of glucocorticoids, could be such a mediator. We show that ANX1 induces a dose- and time-dependent decrease in L-selectin expression on both peripheral blood neutrophils and monocytes but has no effect on lymphocytes. The loss of L-selectin from neutrophils is due to shedding that is mediated by a cell surface metalloprotease ("sheddase"). Using cell shape and a beta(2) integrin activation epitope, we show that the ANX1-induced shedding of L-selectin appears to occur without overt cell activation. These data may provide the basis for further understanding of mechanisms involved in the down-regulation of inflammatory responses.
Strausbaugh
H J
HJ
Department of Anatomy, Program in Immunology and Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
Rosen
S D
SD
D000818:Animals; D017302:Annexins / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D002417:Cattle; D048429:Cell Size / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D019041:L-Selectin / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008666:Metalloendopeptidases / Q000502:physiology; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017302:Annexins; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D019041:L-Selectin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003907:Dexamethasone; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate