Akt1 is critical for acute inflammation and histamine-mediated vascular leakage.
Akt1 is implicated in cell metabolism, survival migration, and gene expression; however, little is known about the role of specific Akt isoforms during inflammation in vivo. Thus, we directly explored the roles of the isoforms Akt1 and Akt2 in acute inflammation models by using mice deficient in either Akt1 or Akt2. Akt1(-/-) mice showed a markedly reduced edema versus Akt2(-/-) and WT controls, and the reduced inflammation was associated with a dramatic decrease in neutrophil and monocyte infiltration. The loss of Akt1 did not affect leukocyte functions in vitro, and bone marrow transplant experiments suggest that host Akt1 regulates leukocyte emigration into inflamed tissues. Moreover, carrageenan-induced edema and the direct propermeability actions of bradykinin and histamine were reduced dramatically in Akt1(-/-) versus WT mice. These findings are supported by in vitro experiments showing that Akt1 deficiency or blockade of nitric oxide synthase markedly reduces histamine-stimulated changes in transendothelial electrical resistance of microvascular endothelial cells. Collectively, these results suggest that Akt1 is necessary for acute inflammation and exerts its actions primarily via regulation of vascular permeability, leading to edema and leukocyte extravasation.
Di Lorenzo
Annarita
A
Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Fernández-Hernando
Carlos
C
Cirino
Giuseppe
G
Sessa
William C
WC
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability / Q000187:drug effects*; D002351:Carrageenan / Q000633:toxicity; D002465:Cell Movement / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006632:Histamine / Q000494:pharmacology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002351:Carrageenan; D006632:Histamine; D009195:Peroxidase; D051057:Proto-Oncogene Proteins c-akt; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse