Monocyte derived microvesicles deliver a cell death message via encapsulated caspase-1.
Apoptosis depends upon the activation of intracellular caspases which are classically induced by either an intrinsic (mitochondrial based) or extrinsic (cytokine) pathway. However, in the process of explaining how endotoxin activated monocytes are able to induce apoptosis of vascular smooth muscle cells when co-cultured, we uncovered a transcellular apoptosis inducing pathway that utilizes caspase-1 containing microvesicles. Endotoxin stimulated monocytes induce the cell death of VSMCs but this activity is found in 100,000 g pellets of cell free supernatants of these monocytes. This activity is not a direct effect of endotoxin, and is inhibited by the caspase-1 inhibitor YVADcmk but not by inhibitors of Fas-L, IL-1beta and IL-18. Importantly, the apoptosis inducing activity co-purifies with 100 nm sized microvesicles as determined by TEM of the pellets. These microvesicles contain caspase-1 and caspase-1 encapsulation is required since disruption of microvesicular integrity destroys the apoptotic activity but not the caspase-1 enzymatic activity. Thus, monocytes are capable of delivering a cell death message which depends upon the release of microvesicles containing functional caspase-1. This transcellular apoptosis induction pathway describes a novel pathway for inflammation induced programmed cell death.
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
Anasuya
A
Sarkar
Srabani
S
Mitra
Sonya
S
Mehta
Raquel
R
Raices
Mark D
MD
Wewers
D017209:Apoptosis; D020170:Caspase 1 / Q000378:metabolism*; D002384:Catalysis; D016923:Cell Death; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000166:cytology
D017077:Culture Media, Conditioned; D016207:Cytokines; D004731:Endotoxins; D020170:Caspase 1