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Roles of Stat3 and ERK in G-CSF Signaling

^a The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan;
^b Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;
^c Department of Pathology, Asahikawa Medical College, Asahikawa, Japan;
^d Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
^e Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan

Key Words. Signal transduction • Hematopoiesis • Signal transducer and activator of transcription • Mitogen-activated protein kinase • G-CSF

Correspondence: Kazuya Shimoda, M.D., The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Telephone: 81-92-642-5230; Fax: 81-92-642-5247; e-mail: kshimoda{at}intmed1.med.kyushu-u.ac.jp

G-CSF specifically stimulates the proliferation and differentiation of cells that are committed to the neutrophil-granulocyte lineage. Although Stat3 was thought to be essential for the transduction of G-CSF–induced cell proliferation and differentiation signals, mice deficient for Stat3 in hematopoietic cells show neutrocytosis and infiltration of cells into the digestive tract. The number of progenitor cells in the neutrophil lineage is not changed, and G-CSF–induced proliferation of progenitor cells and prolonged neutrophil survival were observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3-null bone marrow cells displayed a significant activation of extra-cellular regulated kinase 1 (ERK1)/ERK2 under basal conditions, and the activation of ERK was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. These results indicate that Stat3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression and that ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.

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