title: Cytokine-induced myeloid differentiation is dependent on activation of the MEK/ERK pathway.
abstract: The intracellular signaling pathways that mediate cytokine-induced granulocytic and monocytic differentiation are incompletely understood. In this study, we examined the importance of the MEK/ERK signal transduction pathway in granulocyte-colony stimulating factor (G-CSF)-induced granulocytic differentiation of murine 32 Dc l3 cells, and in interleukin-6 (IL-6)-induced monocytic differentiation of murine M1 cells. Induction of granulocytic differentiation with G-CSF, or monocytic differentiation with IL-6, led to rapid and sustained activation of the MEK-1/-2 and ERK-1/-2 enzymes. Inhibition of the MEK/ERK pathway by pretreatment with the MEK inhibitor U 0126 dramatically attenuated G-CSF-induced granulocytic differentiation and IL-6-induced monocytic differentiation. Inhibition of MEK/ERK signaling also significantly reduced cytokine-induced DNA binding activities of STAT 3 and PU.1, transcription factors that have been implicated in myeloid differentiation. Additionally, interleukin-3, which inhibits G-CSF-induced differentiation of 32 Dc l3 cells, also inhibited the ability of G-CSF to stimulate prolonged MEK/ERK activation. Thus, the opposing actions of different hematopoietic cytokines on myeloid progenitors may be mediated at the level of MEK/ERK activation. Taken together, these studies demonstrate an important requirement for MEK/ERK activation during cytokine-induced granulocytic and monocytic differentiation.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Miranda
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: James A
authors.initials: JA
authors.lastname: Torchia
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000187:drug effects* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018952:Antigens, CD34; D048049:Extracellular Signal-Regulated MAP Kinases; D016179:Granulocyte Colony-Stimulating Factor; D007377:Interleukin-3; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494087:Stat3 protein, mouse