Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses.
The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be activated by different classes of inflammatory stimuli, namely, chemoattractants and growth factors. After stimulation with such agents, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the inducible phosphorylation of ERK occurring in response to these stimuli but had little or no effect on that of p38 MAPK or PI3K. Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF. Moreover, both TAK1 and the MEK/ERK module were found to influence inflammatory cytokine expression and release in fMLF- and GM-CSF-activated neutrophils, whereas the PI3K pathway influenced this response independently of TAK1. Besides cytokine production, other responses were found to be under TAK1 control in neutrophils stimulated with chemoattractants and/or GM-CSF, namely, delayed apoptosis and leukotriene biosynthesis. Our data further emphasize the central role of TAK1 in controlling signaling cascades and functional responses in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions.
Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; Centre de Recherche du CHUS, Sherbrooke, Québec J1H 5N4, Canada;
Stéphanie
S
Sylvain-Prévost
Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; Centre de Recherche du CHUS, Sherbrooke, Québec J1H 5N4, Canada;
Thornin
T
Ear
Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; Centre de Recherche du CHUS, Sherbrooke, Québec J1H 5N4, Canada;
François A
FA
Simard
Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; Centre de Recherche du CHUS, Sherbrooke, Québec J1H 5N4, Canada;
Carl F
http://orcid.org/0000-0002-4495-7408
CF
Fortin
Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; Centre de Recherche du CHUS, Sherbrooke, Québec J1H 5N4, Canada;
Claire M
http://orcid.org/0000-0002-0751-2821
CM
Dubois
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec J1H 5N4, Canada; and Faculté de Médecine, Université Laval, Québec, Québec J1H 5N4, Canada.
Nicolas
N
Flamand
Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada; Centre de Recherche du CHUS, Sherbrooke, Québec J1H 5N4, Canada; patrick.mcdonald@USherbrooke.ca.
Patrick P
PP
McDonald
D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D015289:Leukotrienes / Q000096:biosynthesis; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
D048049:Extracellular Signal-Regulated MAP Kinases; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015289:Leukotrienes; D048728:MAP Kinase Kinase Kinase 1; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D015025:Zearalenone; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C482576:MAP3K1 protein, human; C482625:MAP3K3 protein, human