The involvement of the apoptosis-modulating proteins ERK 1/2, Bcl-xL and Bax in the resolution of acute inflammation in vivo.
Inflammatory cell recruitment, activation, and apoptosis are highly regulated processes involving several checkpoints controlling the resolution of inflammation. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway (ie, ERK1/2) and apoptosis-regulating Bcl-2 family members (ie, Bcl-x(L) and Bax) in the resolution of a rat carrageenan-induced pleurisy model. The specific ERK1/2 inhibitor PD98059 enhanced the resolution of inflammation, whereas the MEK1/2 inhibitor U0126 had no effect and the flavonoid apigenin, a nonspecific inhibitor of ERK1/2 and COX-2, augmented inflammation. Specifically, PD98059 significantly decreased the total number of macrophages and neutrophils in the pleural cavity, mainly by increasing the rate of neutrophil apoptosis, as measured by Annexin V labeling and morphological analysis. Conversely, a specific inhibitor of proapoptotic Bax (V5) increased inflammation, indicating that by preventing apoptosis in vivo, resolution of inflammation is delayed. This was associated with a decrease in neutrophil apoptosis and an increase in macrophage and neutrophil numbers perpetuating the inflammatory response. In conclusion, this study shows that ERK1/2, Bax, and Bcl-x(L) play important functional roles in the resolution phase of the acute inflammatory response in vivo by influencing apoptosis. Importantly, these data may provide novel therapeutic targets for the treatment of inflammatory diseases.
Sawatzky
Deborah A
DA
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh, Scotland, UK EH16 4TJ. d.a.sawatzky@ed.ac.uk
Willoughby
Derek A
DA
Colville-Nash
Paul R
PR
Rossi
Adriano G
AG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002351:Carrageenan / Q000009:adverse effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010998:Pleurisy / Q000209:etiology / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism*; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002351:Carrageenan; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one