title: IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation.
abstract: Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting. In this article, we report that the conversion of murine neutrophil function occurs in bone marrow, and that IL-6 cooperation with G-CSF is required for this conversion. IL-6 cooperated with G-CSF to modulate neutrophils in bone marrow, altering the activation potential of signaling pathways in neutrophils, especially that of STAT3. Costimulation with G-CSF and IL-6 induced a higher level of phospho-STAT3 in neutrophils, which was further increased by upregulation of STAT3 expression in neutrophils owing to downregulation of IFN-β expression in bone marrow macrophages by IL-6. Augmented STAT3 activation was crucial for upregulating the expression of Mmp9 and Bv8 genes and downregulating the expression of Trail and Rab27a genes in neutrophils. Moreover, G-CSF/IL-6-modulated neutrophils could not efficiently release azurophilic granules because of downregulation of Rab27a and inefficient activation of PI3K and p38 MAPK pathways. Because of premodulation by G-CSF and IL-6, neutrophils in response to complex stimuli in tumor released much less myeloperoxidase, neutrophil elastase, and TRAIL, but showed much higher expression of Mmp9 and Bv8 genes. Taken together, these results demonstrate that G-CSF and IL-6, despite their well-known physiological functions, could modulate the activation potential of signaling pathways in neutrophils, resulting in the production or release of the above-mentioned factors in a way that favors tumor angiogenesis and tumor growth.
authors: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors: Bin
authors: B
authors: Yan
authors: Jing-Jing
authors: JJ
authors: Wei
authors: Ye
authors: Y
authors: Yuan
authors: Rui
authors: R
authors: Sun
authors: Dong
authors: D
authors: Li
authors: Jing
authors: J
authors: Luo
authors: Sheng-Jun
authors: SJ
authors: Liao
authors: Yuan-Hong
authors: YH
authors: Zhou
authors: Yu
authors: Y
authors: Shu
authors: Qi
authors: Q
authors: Wang
authors: Gui-Mei
authors: GM
authors: Zhang
authors: Zuo-Hua
authors: ZH
authors: Feng
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D016899:Interferon-beta / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D005768:Gastrointestinal Hormones; D015850:Interleukin-6; D009479:Neuropeptides; C486586:Prok2 protein, mouse; D050796:STAT3 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D000075745:rab27 GTP-Binding Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins