title: Runt-related Transcription Factor 1 (RUNX1) Binds to p50 in Macrophages and Enhances TLR4-triggered Inflammation and Septic Shock.
abstract: An appropriate inflammatory response plays critical roles in eliminating pathogens, whereas an excessive inflammatory response can cause tissue damage. Runt-related transcription factor 1 (RUNX1), a master regulator of hematopoiesis, plays critical roles in T cells; however, its roles in Toll-like receptor 4 (TLR4)-mediated inflammation in macrophages are unclear. Here, we demonstrated that upon TLR4 ligand stimulation by lipopolysaccharide (LPS), macrophages reduced the expression levels of RUNX1 Silencing of Runx1 attenuated the LPS-induced IL-1β and IL-6 production levels, but the TNF-α levels were not affected. Overexpression of RUNX1 promoted IL-1β and IL-6 production in response to LPS stimulation. Moreover, RUNX1 interacted with the NF-κB subunit p50, and coexpression of RUNX1 with p50 further enhanced the NF-κB luciferase activity. Importantly, treatment with the RUNX1 inhibitor, Ro 5-3335, protected mice from LPS-induced endotoxic shock and substantially reduced the IL-6 levels. These findings suggest that RUNX1 may be a new potential target for resolving TLR4-associated uncontrolled inflammation and preventing sepsis.
authors: From the Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Rd. II, Shanghai 200025 and.
authors: Mao-Cai
authors: MC
authors: Luo
authors: From the Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Rd. II, Shanghai 200025 and.
authors: Si-Yuan
authors: SY
authors: Zhou
authors: From the Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Rd. II, Shanghai 200025 and.
authors: Dan-Ying
authors: DY
authors: Feng
authors: the Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Rd., Shanghai 200031, China.
authors: Jun
authors: J
authors: Xiao
authors: the Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Rd., Shanghai 200031, China.
authors: Wei-Yun
authors: WY
authors: Li
authors: From the Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Rd. II, Shanghai 200025 and.
authors: Chun-Di
authors: CD
authors: Xu
authors: the Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Rd., Shanghai 200031, China hongyanwang@sibcb.ac.cn.
authors: Hong-Yan
authors: HY
authors: Wang
authors: From the Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Rd. II, Shanghai 200025 and zhoutong_cn@hotmail.com.
authors: Tong
authors: T
authors: Zhou
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*
chemical_list: D001570:Benzodiazepinones; D050676:Core Binding Factor Alpha 2 Subunit; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011758:Pyrroles; C493726:Runx1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C577686:interleukin-6, mouse; C073701:Nfkb1 protein, mouse; C072173:Ro 5-3335
keywords: NF-κB (NF-KB); RUNX1; Toll-like receptor 4 (TLR4); inflammation; lipopolysaccharide (LPS); p50; sepsis