Effects of decreased calmodulin protein on the survival mechanisms of alveolar macrophages during Pneumocystis pneumonia.
Pneumocystis infection causes increased intracellular levels of reactive oxygen species (ROS) and the subsequent apoptosis of alveolar macrophages (Amø). Assessments of key prosurvival molecules in Amø and bronchoalveolar lavage fluids from infected rats and mice showed low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced activation of phosphoinositide-3 kinase (PI-3K). Ubiquitous calcium-sensing protein calmodulin protein and mRNA levels were also reduced in Amø during Pneumocystis pneumonia (Pcp). Calmodulin has been implicated in control of GM-CSF production and PI-3K activation in other immune cell types. Experiments to determine the control of GM-CSF and PI-3K by calmodulin in Amø showed that GM-CSF expression and PI-3K activation could not be induced when calmodulin was inhibited. Calmodulin inhibition also led to increased levels of ROS and apoptosis in cells exposed to bronchoalveolar lavage fluids from infected animals. Supplementation of Amø with exogenous calmodulin increased survival signaling via GM-CSF and PI-3K and reduced ROS and apoptosis. These data support the hypotheses that calmodulin levels at least partially control survival signaling in Amø and that restoration of GM-CSF or PI-3K signaling will improve host response to the organism.
Lasbury
Mark E
ME
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, 46202-5112, USA. melasbur@iupui.edu
Durant
Pamela J
PJ
Liao
Chung-Ping
CP
Lee
Chao-Hung
CH
D000818:Animals; D017209:Apoptosis; D002147:Calmodulin / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D011020:Pneumonia, Pneumocystis / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis
D002147:Calmodulin; D017382:Reactive Oxygen Species; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases