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

BMC Cell Biology

Claes Dahlgren¹  Anna Karlsson¹  Kristoffer Hellstrand⁴  Ulf-Henrik Mellqvist³  Huamei Fu¹  Sara Pellmé¹  Johan Bylund² 

[1] Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden;Department of Paediatrics, University of British Columbia, BC Research Institute for Children's and Woman's Health, Vancouver, British Columbia, Canada V5Z 4H4;Department of Hematology, University of Göteborg, Göteborg, Sweden;Department of Virology, University of Göteborg, Göteborg, Sweden

关键词: NADPH-oxidase;    GPCR;    G. protein;    pertussis toxin;    receptor reactivation;    cytoskeleton;    TNF;    priming;    superoxide;    cytokines;   

Others  :  1088901
DOI  :  10.1186/1471-2121-5-21

 received in 2004-03-13, accepted in 2004-05-24,  发布年份 2004

【 摘 要 】

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.

【 授权许可】

   
2004 Bylund et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

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