Endothelial cells and extracellular calmodulin inhibit monocyte tumor necrosis factor release and augment neutrophil elastase release.
Cultured human umbilical vein endothelial cells inhibited tumor necrosis factor-alpha release from whole blood or isolated mononuclear cells exposed to endotoxin. In contrast, the endothelial cells augmented neutrophil elastase release in the same blood. A protein with these functional properties was isolated from endothelial cell-conditioned media and, surprisingly, was identified as calmodulin. Authentic calmodulin mimicked the effect of endothelium. 125I-Calmodulin bound to a high affinity site on monocytic cell lines (Kd approximately 30 nM, in agreement with its functional activity). Cross-linking of 125I-calmodulin to monocytic cells identified a candidate calmodulin receptor. We conclude that calmodulin possesses an extracellular signaling role in addition to its intracellular regulatory functions. Calmodulin released at sites of tissue injury or possibly by specific mechanisms in the endothelium can bind to receptors, modulating the activities of inflammatory cells.
Houston
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DS
Department of Internal Medicine and Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada. houston@umanitoba.ca
Carson
C W
CW
Esmon
C T
CT
D000595:Amino Acid Sequence; D000818:Animals; D002147:Calmodulin / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D002148:Calmodulin-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004730:Endothelium, Vascular / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000097:blood*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014471:Umbilical Veins
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D003432:Cross-Linking Reagents; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019272:Leukocyte Elastase