Spatial and temporal profiles for anti-inflammatory gene expression in leukocytes during a resolving model of peritonitis.
The recent appreciation of the role played by endogenous counterregulatory mechanisms in controlling the outcome of the host inflammatory response requires specific analysis of their spatial and temporal profiles. In this study, we have focused on the glucocorticoid-regulated anti-inflammatory mediator annexin 1. Induction of peritonitis in wild-type mice rapidly (4 h) produced the expected signs of inflammation, including marked activation of resident cells (e.g., mast cells), migration of blood-borne leukocytes, mirrored by blood neutrophilia. These changes subsided after 48-96 h. In annexin 1(null) mice, the peritonitis response was exaggerated ( approximately 40% at 4 h), with increased granulocyte migration and cytokine production. In blood leukocytes, annexin 1 gene expression was activated at 4, but not 24, h postzymosan, whereas protein levels were increased at both time points. Locally, endothelial and mast cell annexin 1 gene expression was not detectable in basal conditions, whereas it was switched on during the inflammatory response. The significance of annexin 1 system plasticity in the anti-inflammatory properties of dexamethasone was assessed. Clear induction of annexin 1 gene in response to dexamethasone treatment was evident in the circulating and migrated leukocytes, and in connective tissue mast cells; this was associated with the steroid failure to inhibit leukocyte trafficking, cytokine synthesis, and mast cell degranulation in the annexin 1(null) mouse. In conclusion, understanding how inflammation is brought under control will help clarify the complex interplay between pro- and anti-inflammatory pathways operating during the host response to injury and infection.
William Harvey Research Institute, London, UK.
Amilcar S
AS
Damazo
Simon
S
Yona
Roderick J
RJ
Flower
Mauro
M
Perretti
Sonia M
SM
Oliani
D000818:Animals; D017305:Annexin A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D010538:Peritonitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors
D017305:Annexin A1; D018836:Inflammation Mediators; D003907:Dexamethasone