title: Stress-induced NF-κB activation differentiates promyelocytic leukemia cells to macrophages in response to all-trans-retinoic acid.
abstract: All-trans-retinoic acid (ATRA) has been known as a choice of treatment for inducing differentiation of promyelocytic leukemia cells to granulocytes. NF-κB plays a crucial role in inflammation and immunity and its activation is an important event for macrophage differentiation both in vivo and in vitro. We report here that NF-κB activation is critical for determining ATRA-induced lineage specific differentiation of myeloid leukemia cells. Our data revealed that ATRA treatment to HL-60 cells enhanced IκBα degradation and NF-κB nuclear translocation and the activated NF-κB potentiated the ability of ATRA for differentiation and switched differentiation to macrophages instead of granulocytes. Serum withdrawal and LPS treatment dampened IκBα expression via MAPK activation and reactive oxygen species generation leading to NF-κB nuclear translocation and ATRA treatment further corroborated these effects in myeloid leukemia cells. Activated NF-κB enhanced the degree of ATRA-induced differentiation of HL-60 cells to macrophages, rather than granulocytes, as assessed by morphologic examination and expressions of differentiation markers such as CD11b, CD38, CD68, MMP9 and Btg2. Employing LLnL or dominant negative IκBα attenuated NF-κB associated enhanced cell maturation and differentiation switch thus suggesting NF-κB as one of the factors that determines ATRA induced lineage specificity of myeloid leukemia cells. Furthermore, MAPK activation was observed to be central both for the differentiation of promyelocytic cells to macrophages or granulocytes regulating NF-κB or C/EBPα expressions, respectively; however, MAPK-mediated signals are modulated under various conditions affecting lineage specificity. In summary, our present data demonstrate that activation of NF-κB directly affects differentiation program of promyelocytes to macrophages, rather than granulocyte, in response to ATRA treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Molecular Medicine, Ajou University School of Medicine and Graduate School, Suwon 443-380, Republic of Korea; Biochemistry Section, Institute of Chemical Sciences, Faculty of Life and Environmental Sciences, University of Peshawar, Peshawar 25120, KP, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran
authors.affiliation: Department of Hematology and Oncology, Ajou University School of Medicine and Graduate School, Suwon 443-380, Republic of Korea.
authors.forename: Joon Seong
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Molecular Medicine, Ajou University School of Medicine and Graduate School, Suwon 443-380, Republic of Korea. Electronic address: iklim@ajou.ac.kr.
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D022762:CCAAT-Enhancer-Binding Proteins; D039481:CD11b Antigen; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D020780:Matrix Metalloproteinase 9; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014212:Tretinoin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000606204:NFKBIA protein, human
keywords: Differentiation; Granulocytes; Macrophages; NF-κB; Retinoic acid; Stress conditions