Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse.
The 37-kDa protein annexin 1 (Anx-1; lipocortin 1) has been implicated in the regulation of phagocytosis, cell signaling, and proliferation and is postulated to be a mediator of glucocorticoid action in inflammation and in the control of anterior pituitary hormone release. Here, we report that mice lacking the Anx-1 gene exhibit a complex phenotype that includes an altered expression of other annexins as well as of COX-2 and cPLA2. In carrageenin- or zymosan-induced inflammation, Anx-1-/- mice exhibit an exaggerated response to the stimuli characterized by an increase in leukocyte emigration and IL-1beta generation and a partial or complete resistance to the antiinflammatory effects of glucocorticoids. Anx-1-/- polymorphonuclear leucocytes exhibited increased spontaneous migratory behavior in vivo whereas in vitro, leukocytes from Anx-1-/- mice had reduced cell surface CD 11b (MAC-1) but enhanced CD62L (L-selectin) expression and Anx-1-/- macrophages exhibited anomalies in phagocytosis. There are also gender differences in activated leukocyte behavior in the Anx-1-/- mice that are not seen in the wild-type animals, suggesting an interaction between sex hormones and inflammation in Anx-1-/- animals.
Hannon
Robert
R
Department of Biochemical Pharmacology, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, EC1M 6BQ, UK.
Croxtall
Jamie D
JD
Getting
Steve J
SJ
Roviezzo
Fiorita
F
Yona
Simon
S
Paul-Clark
Mark J
MJ
Gavins
Felicity N E
FN
Perretti
Mauro
M
Morris
John F
JF
Buckingham
Julia C
JC
Flower
Roderick J
RJ
D000818:Animals; D017305:Annexin A1 / Q000235:genetics* / Q000378:metabolism; D002351:Carrageenan; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010741:Phospholipases A / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors
D017305:Annexin A1; D015815:Cell Adhesion Molecules; D005938:Glucocorticoids; D007375:Interleukin-1; D007527:Isoenzymes; D003907:Dexamethasone; D002351:Carrageenan; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A