TY - JOUR
T1 - G-CSF-activated STAT3 enhances production of the chemokine MIP-2 in bone marrow neutrophils
AU - Nguyen-Jackson, Hoainam T.
AU - Li, Haiyan S.
AU - Zhang, Huiyuan
AU - Ohashi, Erika
AU - Watowich, Stephanie S.
PY - 2012/12/1
Y1 - 2012/12/1
N2 - Neutrophil mobilization from the bone marrow is a critical aspect of the innate immune response, enabling a rapid deployment of phagocytes to infected or inflamed tissue. The cytokine G-CSF, which is induced rapidly during infection, elicits a swift and potent mobilizing response, yet its mechanisms of action remain poorly understood. Here, we studied the role of G-CSF and its principal signal transducer STAT3 in regulating expression of the neutrophil chemoattractant MIP-2. Our studies revealed Gr-1hi mature neutrophils as major sources of Cxcl2 (MIP-2) mRNA in bone marrow and G-CSF-responsive MIP-2 protein production. Induction of Cxcl2 was regulated directly by G-CSF-activated STAT3 via interaction at a STAT consensus element in the Cxcl2 promoter. G-CSF coordinately stimulated the association of STAT3, induction of the transcriptionally active H3K4me3 modification, and recruitment of RNA Pol II at the Cxcl2 proximal promoter, as well as the promoter region of Il8rb, encoding the MIP-2 receptor. These results suggest that the G-CSF-STAT3 pathway directly regulates transcriptional events that induce neutrophil mobilization.
AB - Neutrophil mobilization from the bone marrow is a critical aspect of the innate immune response, enabling a rapid deployment of phagocytes to infected or inflamed tissue. The cytokine G-CSF, which is induced rapidly during infection, elicits a swift and potent mobilizing response, yet its mechanisms of action remain poorly understood. Here, we studied the role of G-CSF and its principal signal transducer STAT3 in regulating expression of the neutrophil chemoattractant MIP-2. Our studies revealed Gr-1hi mature neutrophils as major sources of Cxcl2 (MIP-2) mRNA in bone marrow and G-CSF-responsive MIP-2 protein production. Induction of Cxcl2 was regulated directly by G-CSF-activated STAT3 via interaction at a STAT consensus element in the Cxcl2 promoter. G-CSF coordinately stimulated the association of STAT3, induction of the transcriptionally active H3K4me3 modification, and recruitment of RNA Pol II at the Cxcl2 proximal promoter, as well as the promoter region of Il8rb, encoding the MIP-2 receptor. These results suggest that the G-CSF-STAT3 pathway directly regulates transcriptional events that induce neutrophil mobilization.
KW - Chemotaxis
KW - Chromatin
KW - Transcription
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U2 - 10.1189/jlb.0312126
DO - 10.1189/jlb.0312126
M3 - Article
C2 - 23024284
AN - SCOPUS:84870411737
SN - 0741-5400
VL - 92
SP - 1215
EP - 1225
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 6
ER -