TAK1 knockdown enhances lipopolysaccharide-induced secretion of proinflammatory cytokines in myeloid cells via unleashing MEKK3 activity.
TGF-β activating protein kinase 1 (TAK1) belongs to the MAP kinase kinase kinase (MAP3K) family. TAK1 is involved in many signaling pathways, especially the innate and adaptive immune responses. TAK1 mediates nuclear factor κB (NF-κB) and MAPK signaling pathway in response to interleukin-1, tumor necrosis factor-α (TNFα), and toll-like receptor agonists, such as lipopolysaccharide (LPS). The regulatory roles of TAK1 in LPS-induced proinflammatory cytokines production are dependent on the cell types. In this study, we examined the effects of TAK1 on the LPS induced production of proinflammatory cytokines in myeloid cells. Knockdown of TAK1 enhanced the secretion of interleukin 1-beta (IL-1β) and TNFα induced by LPS. In addition, LPS-activated TAK1 negatively regulates mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). Moreover, TAK1 inhibited MEKK3 activation, which, in turn, activated NF-κB. These results indicate that TAK1 negatively regulates LPS-induced cytokine secretion in myeloid cells by inhibiting MEKK3 activities.
Institute of Immunology, College of Life Science & Technology, Dalian University, Dalian, Liaoning, China; College of Medicine, Dalian University, Dalian, Liaoning, China.
Kun
K
Li
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, United States.
Meichen
M
Wang
Institute of Immunology, College of Life Science & Technology, Dalian University, Dalian, Liaoning, China.
Yaping
Y
Hu
Institute of Immunology, College of Life Science & Technology, Dalian University, Dalian, Liaoning, China.
Na
N
Xu
Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, China.
Qin
Q
Yu
Institute of Immunology, College of Life Science & Technology, Dalian University, Dalian, Liaoning, China. Electronic address: qinfuwang@126.com.
Qinfu
Q
Wang
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism; D000067996:RAW 264.7 Cells; D034741:RNA, Small Interfering / Q000235:genetics; D000099151:MAP Kinase Kinase Kinase 7
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000099151:MAP Kinase Kinase Kinase 7; C482626:Map3k3 protein, mouse
Lipopolysaccharide (LPS); Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3); Myeloid cell; TGF-β activating protein kinase 1 (TAK1); Toll-like receptor 4 (TLR4)