title: Crosstalk between JNK and NF-κB in the KDO2-mediated production of TNFα in HAPI cells.
abstract: Both nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases mediate production of proinflammatory cytokines in many types of cells. c-Jun N-terminal kinases (JNK) is a key regulator of many cellular events including cell inflammation and/or programmed cell death (apoptosis). In addition to mediating immune and inflammatory responses, NF-κB transcription factors control cell survival. It is reported that activation of NF-κB antagonizes apoptosis or programmed cell death by numerous triggers. It has been reported that NF-κB activation results in rapid inactivation of JNK in tumor necrosis factor alpha (TNFα)-treated murine embryonic fibroblasts. It is not clear about the relationship of JNK and NF-κB in the microglial cells induced by TLR4 activity. In the present study, we investigated the relationship of JNK and NF-κB in the highly aggressively proliferating immortalized microglial cell line treated with KDO2 (a TLR4 agonist). KDO2 treatment significantly induced the phosphorylation of JNK and NF-κB, and released TNFα. Knockdown of TLR4 with TLR4 siRNA significantly reduced phosphorylation of JNK (pJNK), phosphorylation of NF-κB, and release of TNFα. Inhibition of JNK reduced the release of TNFα, but not phosphorylation of NF-κB. Unexpectedly, inhibition of NF-κB enhanced pJNK and the release of TNFα. These results showed that TNFα induced by KDO2 was JNK-dependent, and that NF-κB negatively modulated both pJNK and TNFα in the cultured microglial cell line. The current study may provide a new insight in the modulation of TNFα in the microglial cell line.
authors: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Xuexing
authors: X
authors: Zheng
authors: Wenwen
authors: W
authors: Zheng
authors: Shue
authors: S
authors: Liu
authors: Harshil M
authors: HM
authors: Patel
authors: Xianzhu
authors: X
authors: Xia
authors: Hongsheng
authors: H
authors: Ouyang
authors: Roy C
authors: RC
authors: Levitt
authors: Keith A
authors: KA
authors: Candiotti
authors: Shuanglin
authors: S
authors: Hao
mesh_terms: D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: C506188:Kdo2-lipid A; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4