title: Celastrol inhibits lung infiltration in differential syndrome animal models by reducing TNF-α and ICAM-1 levels while preserving differentiation in ATRA-induced acute promyelocytic leukemia cells.
abstract: All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China; Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China.
authors.forename: Li-min
authors.initials: LM
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China; Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yue-juan
authors.initials: YJ
authors.lastname: Zheng
authors.affiliation: Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China.
authors.forename: Fan-fan
authors.initials: FF
authors.lastname: Cao
authors.affiliation: Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xiong-fei
authors.initials: XF
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Hua-zhang
authors.initials: HZ
authors.lastname: An
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Ao-xiang
authors.initials: AX
authors.lastname: Zheng
authors.affiliation: Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China; U972, Inserm, Hôpital Paul Brousse, Paris, France.
authors.forename: Deng-hai
authors.initials: DH
authors.lastname: Zhang
authors.affiliation: Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, Shanghai, China; U972, Inserm, Hôpital Paul Brousse, Paris, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Yi-zhi
authors.initials: YZ
authors.lastname: Yu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D014212:Tretinoin / Q000009:adverse effects* / Q000627:therapeutic use; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D014212:Tretinoin; C050414:celastrol