Granulocyte colony-stimulating factor negatively regulates Toll-like receptor agonist-induced cytokine production in human neutrophils.
We studied the effect of G-CSF on TLR agonist-induced cytokine production in human neutrophils. Human neutrophils produced IL-8 and TNF-alpha in response to stimulation with TLR agonists such as LPS and N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine. This response was dependent on activation of ERK, p38, and PI3K, but not JNK. TLR agonist-induced cytokine production in neutrophils was inhibited by G-CSF, whereas it was enhanced by GM-CSF, and GM-CSF-mediated enhancement was attenuated by G-CSF. G-CSF and GM-CSF did not affect TLR agonist-induced phosphorylation of ERK, p38, JNK, Akt, and IkappaBalpha. STAT3 activation was much greater in G-CSF-stimulated neutrophils than that in GM-CSF-stimulated cells. G-CSF-mediated STAT3 phosphorylation and inhibition of TLR agonist-induced cytokine production were prevented by pretreatment of cells with AG-490 (JAK2 inhibitor). These findings suggest that G-CSF and GM-CSF exert the opposite effects on TLR agonist-induced cytokine production, and G-CSF negatively regulates TLR agonist-induced cytokine production in neutrophils via activation of STAT3.
Fukuzono
Shunsuke
S
Department of Physiology, Osaka City University Graduate School of Medicine, Asahi-machi, Abeno-ku, Japan.
Kato
Takayuki
T
Fujita
Hisakazu
H
Watanabe
Norifumi
N
Kitagawa
Seiichi
S
D016207:Cytokines / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D053614:Janus Kinase 2 / Q000276:immunology; D055666:Lipopeptides / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D016207:Cytokines; D016209:Interleukin-8; D055666:Lipopeptides; D008070:Lipopolysaccharides; D016328:NF-kappa B; C508075:Pam(3)CSK(4) peptide; D050796:STAT3 Transcription Factor; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases