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Cytochalasin B triggers a novel pertussis toxin sensitive pathway in TNF-alpha primed neutrophils

Journal article
Authors Johan Bylund
Sara Pellmé
Huamei Fu
Ulf-Henrik Mellqvist
Kristoffer Hellstrand
Anna Karlsson
Claes Dahlgren
Published in BMC cell biology
Volume 5
Pages 21
ISSN 1471-2121 (Electronic)
Publication year 2004
Published at Institute of Internal Medicine, Dept of Rheumatology and Inflammation Research
Institute of Internal Medicine, Dept of Medicine
Institute of Laboratory Medicine, Dept of Clinical Virology
Pages 21
Language en
Keywords Cyclosporine/pharmacology, Cytochalasin B/*pharmacology, Humans, Imidazoles/pharmacology, NADPH Oxidase/metabolism, Neutrophil Activation/physiology, Neutrophils/*drug effects/enzymology/*physiology, Peptide Fragments/immunology, Pertussis Toxin/*immunology, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Pyridines/pharmacology, Receptors, Formyl Peptide/antagonists & inhibitors/physiology, Receptors, G-Protein-Coupled/physiology, Respiratory Burst/drug effects, Secretory Vesicles/metabolism, Signal Transduction/*physiology, Tumor Necrosis Factor-alpha/*pharmacology/physiology
Subject categories Immunology in the medical area


BACKGROUND: Cytochalasin B does not directly activate the oxygen-radical-producing NADPH oxidase activity of neutrophils but transfers desensitized G-protein coupled receptors (GPCR) into an active signaling state by uncoupling GCPR from the cytoskeleton. The receptor uncoupling results in respiratory burst activity when signals generated by reactivated formyl peptide receptors trigger the NADPH-oxidase to produce superoxide anions. RESULTS: Tumor necrosis factor alpha (TNF-alpha) primes neutrophils for subsequent activation by cytochalasin B. Pretreatment with TNF-alpha induced mobilization of receptor-storing neutrophil organelles, suggesting that receptor up-regulation significantly contributes to the response, but the receptor mobilization was not sufficient for induction of the cytochalasin B sensitive state. The TNF-alpha primed state resembled that of the desensitized non-signaling state of agonist-occupied neutrophil formyl peptide receptors. The fact that the TNF-alpha primed, cytochalasin B-triggered activation process was pertussis toxin sensitive suggests that the activation process involves a GPCR. Based on desensitization experiments the unidentified receptor was found to be distinct from the C5a receptor as well as the formyl peptide receptor family members FPR and FPRL1. Based on the fact the occupied and desensitized receptors for interleukin-8 and platelet activating factor could not be reactivated by cytochalasin B, also these could be excluded as receptor candidates involved in the TNF-alpha primed state. CONCLUSIONS: The TNF-alpha-induced priming signals could possibly trigger a release of an endogenous GPCR-agonist, amplifying the response to the receptor-uncoupling effect of cytochalasin B. However, no such substance could be found, suggesting that TNF-alpha can transfer G-protein coupled receptors to a signaling state independently of agonist binding.

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