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The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment

Journal article
Authors Lena Björkman
Jonas Martensson
Malene Winther
Michael Gabl
André Holdfeldt
Martin Uhrbom
Johan Bylund
A. H. Hansen
S. K. Pandey
T. Ulven
Huamei Forsman
Claes Dahlgren
Published in Molecular and Cellular Biology
Volume 36
Issue 20
Pages 2583-2595
ISSN 0270-7306
Publication year 2016
Published at Institute of Odontology
Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages 2583-2595
Language en
Keywords formyl peptide receptors, cytosolic-free ca-2+, factor-induced, degranulation, adherent human neutrophils, protein-coupled receptors, nadph-oxidase, respiratory burst, chemoattractant receptors, pyrimidine, nucleotides, activates neutrophils, Biochemistry & Molecular Biology, Cell Biology
Subject categories Biological Sciences


Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, and we here characterize the neutrophil responses induced by one such agonist (Cmp1) and one antagonist (CATPB). Cmp1 triggered an increase in the cytosolic concentration of Ca2+, and the neutrophils were then desensitized to Cmp1 and to acetate, a naturally occurring FFA2R agonist. The antagonist CATPB selectively inhibited responses induced by Cmp1 or acetate. The activated FFA2R induced superoxide anion secretion at a low level in naive blood neutrophils. This response was largely increased by tumor necrosis factor alpha (TNF-alpha) in a process associated with a recruitment of easily mobilizable granules, but neutrophils recruited to an aseptic inflammation in vivo were nonresponding. Superoxide production induced by Cmp1 was increased in latrunculin A-treated neutrophils, but no reactivation of desensitized FFA2R was induced by this drug, suggesting that the cytoskeleton is not directly involved in terminating the response. The functional and regulatory differences between the receptors that recognize short-chain fatty acids and formylated peptides, respectively, imply different roles of these receptors in the orchestration of inflammation and confirm the usefulness of a selective FFA2R agonist and antagonist as tools for the exploration of the precise role of the FFA2R.

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