title: Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients.
abstract: Although increased TNF-α has been considered to cause ineffective hematopoiesis in myelodysplastic syndromes (MDS), the mechanisms of TNF-α elevation are not known. We recently found that c-Fos mRNA stabilization under translation-inhibiting stimuli was impaired in MDS-derived neutrophilic granulocytes. In the current study, we identified overexpression of c-Fos-targeting miR-34a and miR-155 as the cause of impairment. Expression levels of miR-34a but not miR-155 inversely correlated with ratios of c-Fos-positive cells in MDS-derived CD16+ neutrophils (r = -0.618, P<0.05), which were analyzed by flow cytometry. Among the seventeen patients, c-Fos was detectable in less than 60% of CD16+ cells in eight patients (Group A), while five (Group B) expressed c-Fos in more than 80% of CD16+ cells, which was consistent with the controls (88.6 ± 7.8%). Group A-derived granulocytes secreted more TNF-α in response to 1 μM LPS for 3 hours (735.4 ± 237.5 pg/mL) than Group B (143.5 ± 65.7 pg/mL, P<0.05) and healthy controls (150.8 ± 91.5 pg/mL, P<0.05). Knockdown of c-Fos in neutrophil-like differentiated HL60 increased the binding of NF-κB p65 to the promoter region of TNF-α DNA. Thus, c-Fos reduction via overexpression of miR-34a contributes to TNF-α overproduction under inflammatory stimuli in MDS.
authors: Department of Pharmacology, Fukushima Medical University, Fukushima, Japan.
authors: Yayoi
authors: Y
authors: Shikama
authors: Department of Pharmacology, Fukushima Medical University, Fukushima, Japan.
authors: Meiwan
authors: M
authors: Cao
authors: Department of Pharmacology, Fukushima Medical University, Fukushima, Japan.
authors: Tomoyuki
authors: T
authors: Ono
authors: Department of Pharmacology, Fukushima Medical University, Fukushima, Japan.
authors: Xiaomin
authors: X
authors: Feng
authors: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors: Hideyoshi
authors: H
authors: Noji
authors: Department of Hematology, Kita Fukushima Medical Center, Date, Japan.
authors: Hideo
authors: H
authors: Kimura
authors: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors: Kazuei
authors: K
authors: Ogawa
authors: Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima, Japan.
authors: Yuko
authors: Y
authors: Suzuki
authors: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.|Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima, Japan.
authors: Kazuhiko
authors: K
authors: Ikeda
authors: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors: Yasuchika
authors: Y
authors: Takeishi
authors: Department of Pharmacology, Fukushima Medical University, Fukushima, Japan.
authors: Junko
authors: J
authors: Kimura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha