Deficiency in the anti-apoptotic protein A1-a results in a diminished acute inflammatory response.
A1 is an anti-apoptotic member of the Bcl-2 family that is up-regulated in inflammatory myeloid cells. In the present study, we investigated the role of A1 in the maintenance of acute inflammation in mice. Mice possess three genes encoding highly related isoforms of A1. A1-a isoform mRNA was minimally expressed in resident peritoneal macrophages, but was present at a 300-fold higher level in inflammatory macrophages elicited by i.p. infection with Toxoplasma gondii. In comparison, A1-b and A1-d levels were 3- and 10-fold higher, respectively. Peritoneal leukocytosis was decreased in infected A1-a-deficient mice compared with wild-type, and this reduction was associated with a small but reproducible enhancement of survival. These effects could not be explained by an alteration in peritoneal parasite load, nor by increased apoptosis of infected inflammatory cells, which were protected from cell death by an A1-a-independent mechanism. Increased apoptosis in inflammatory neutrophils was observed sporadically in A1-a-deficient mice. Regulation of apoptosis by A1-a may be an important proinflammatory event in acute host responses.
Orlofsky
Amos
A
Department of Pathology, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY 10461, USA. orlofsky@aecom.yu.edu
Weiss
Louis M
LM
Kawachi
Nicole
N
Prystowsky
Michael B
MB
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D005260:Female; D018390:Gene Targeting; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000276:immunology* / Q000469:parasitology; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000648:ultrastructure; D007964:Leukocytosis / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology / Q000469:parasitology / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D010538:Peritonitis / Q000276:immunology / Q000469:parasitology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014122:Toxoplasma / Q000254:growth & development; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000469:parasitology; D015854:Up-Regulation
C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger