Cooperative prosurvival activity by ERK and Akt in human alveolar macrophages is dependent on high levels of acid ceramidase activity.
Human alveolar macrophages are unique in that they have an extended life span in contrast to precursor monocytes. In evaluating the role of sphingolipids in alveolar macrophage survival, we found high levels of sphingosine, but not sphingosine-1-phosphate. Sphingosine is generated by the action of ceramidase(s) on ceramide, and alveolar macrophages have high constitutive levels of acid ceramidase mRNA, protein, and activity. The high levels of acid ceramidase were specific to alveolar macrophages, because there was little ceramidase protein or activity (or sphingosine) in monocytes from matching donors. In evaluating prolonged survival of alveolar macrophages, we observed a requirement for constitutive activity of ERK MAPK and the PI3K downstream effector Akt. Blocking acid ceramidase but not sphingosine kinase activity in alveolar macrophages led to decreased ERK and Akt activity and induction of cell death. These studies suggest an important role for sphingolipids in prolonging survival of human alveolar macrophages via distinct survival pathways.
Monick
Martha M
MM
Division of Pulmonary, Critical Care, and Occupational Medicine, Roy J. and Lucille A. Carver College of Medicine, Eckstein Medical Research Building Room 100, University of Iowa, Iowa City, IA 52242, USA. martha-monick@uiowa.edu
Mallampalli
Rama K
RK
Bradford
Mary
M
McCoy
Diann
D
Gross
Thomas J
TJ
Flaherty
Dawn M
DM
Powers
Linda S
LS
Cameron
Kelli
K
Kelly
Samuel
S
Merrill
Alfred H
AH
Hunninghake
Gary W
GW
D002470:Cell Survival; D002478:Cells, Cultured; D002517:Galactosylgalactosylglucosylceramidase / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D013110:Sphingosine / Q000032:analysis / Q000494:pharmacology
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D002517:Galactosylgalactosylglucosylceramidase; D013110:Sphingosine