title: Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling.
abstract: Bv8, also known as prokineticin 2, has been characterized as an important mediator of myeloid cell mobilization and myeloid cell-dependent tumor angiogenesis. Bv8 expression is dramatically enhanced by G-CSF, both in vitro and in vivo. The mechanisms involved in such up-regulation remain unknown. Using pharmacological inhibitors that interfere with multiple signaling pathways known to be activated by G-CSF, we show that signal transducer and activator of transcription 3 (Stat3) activation is required for Bv8 up-regulation in mouse bone marrow cells, whereas other Stat family members and extracellular signal-regulated kinase (ERK) activation are not involved. We further identified CD11b(+) Gr1(+) myeloid cells as the primary cell population in which Stat3 signaling is activated by G-CSF. Bv8 expression induced by G-CSF was also significantly reduced by siRNA-mediated Stat3 knockdown. Moreover, chromatin immunoprecipitation studies indicate that G-CSF significantly induces binding of phospho-Stat3 to the Bv8 promoter, which was abolished by pretreatment with the Stat3 inhibitor WP1066. Luciferase assay confirmed that the phospho-Stat3 binding site is a functional enhancer of the Bv8 promoter. The key role of Stat3 signaling in regulating G-CSF-induced Bv8 expression was further confirmed by in vivo studies. We show that the regulation of Bv8 expression in human bone marrow cells is also Stat3 signaling-dependent. Stat3 is recognized as a key regulator of inflammation-dependent tumorigenesis. We propose that such a role of Stat3 reflects at least in part its ability to regulate Bv8 expression.
authors.affiliation: Genentech Inc, South San Francisco, California 94080, USA.
authors.forename: Xueping
authors.initials: X
authors.lastname: Qu
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
authors.forename: Lanlan
authors.initials: L
authors.lastname: Yu
authors.forename: Gloria
authors.initials: G
authors.lastname: Meng
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D039481:CD11b Antigen; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D039481:CD11b Antigen; D005768:Gastrointestinal Hormones; C509295:ITGAM protein, human; D009479:Neuropeptides; C423608:PROK2 protein, human; C486586:Prok2 protein, mouse; D011725:Pyridines; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C519885:WP1066; C551746:granulocyte receptor 1, mouse; D016179:Granulocyte Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases