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The mechanism for activation of the neutrophil NADPH-oxidase by the peptides formyl-Met-Leu-Phe and Trp-Lys-Tyr-Met-Val-Met differs from that for interleukin-8

Journal article
Authors Huamei Fu
Johan Bylund
Anna Karlsson
Sara Pellmé
Claes Dahlgren
Published in Immunology
Volume 112
Issue 2
Pages 201-10
ISSN 0019-2805 (Print)
Publication year 2004
Published at Institute of Internal Medicine, Dept of Rheumatology and Inflammation Research
Pages 201-10
Language en
Links www.ncbi.nlm.nih.gov/entrez/query.f...
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Adult, Cells, Cultured, Chemotactic Factors/*immunology, Chemotaxis, Leukocyte/immunology, Cytoskeleton/metabolism, Enzyme Activation/immunology, Humans, Interleukin-8/*immunology, N-Formylmethionine Leucyl-Phenylalanine/immunology, NADPH Oxidase/*metabolism, Neutrophil Activation, Neutrophils/*enzymology/immunology, Oligopeptides/immunology, Platelet Activating Factor/immunology, Receptors, Formyl Peptide/immunology, Receptors, Interleukin-8A/metabolism, Receptors, Interleukin-8B/metabolism, Signal Transduction/immunology, Tumor Necrosis Factor-alpha/immunology
Subject categories Microbiology in the medical area

Abstract

Neutrophil chemotaxis has been shown to be regulated by two different signalling pathways that allow strong chemoattractants, such as bacterial-derived formylated peptides, to dominate over endogenous attractants, such as interleukin-8 (IL-8). Here we show that triggering of the formyl peptide receptor (FPR) with f-Met-Leu-Phe (fMLF) substantially reduced the neutrophil superoxide production induced by activation of the CXC receptors with IL-8. When the order of agonists was reversed, the cells were primed in their response to fMLF, suggesting that the signalling hierarchy between strong, so-called end-type (i.e. fMLF) and weak or intermediate-type (i.e. IL-8) chemoattractants, is also operating during activation of the NADPH-oxidase. The same result was obtained when fMLF was replaced with the hexapeptide, WKYMVM, specific for the formyl peptide-like receptor 1 (FPRL1). There were additional differences between the agonist receptor pairs fMLF/FPR, WKYMVM/FPRL1 and IL-8/CXCR. In contrast to FPR and FPRL1, no reserve pool of CXCR was present in subcellular granules and it was impossible to prime the oxidative response transduced through CXCR by the addition of priming agents such as tumour necrosis factor-alpha and platelet-activating factor. Moreover, the cytoskeleton-disrupting substance, cytochalasin B, had no effect either on IL-8-triggered oxidase activation or on CXCR reactivation. A pertussis toxin-sensitive G-protein is involved in signalling mediated through both FPR and CXCR, and the signalling cascades include a transient intracellular calcium increase, as well as downstream p38 MAPK and phosphoinositide 3-kinase activation. The data presented in this study provide support for two different signalling pathways to the neutrophil NADPH-oxidase, used by ligand binding to FPR/FPRL1 or CXCR, respectively.

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