title: The second-generation mTOR kinase inhibitor INK128 exhibits anti-inflammatory activity in lipopolysaccharide-activated RAW 264.7 cells.
abstract: Cross-talk between the mTOR (mechanistic target of rapamycin) and NF-κB (nuclear factor kappa-B) pathways has been reported to regulate macrophage responses to lipopolysaccharide (LPS). In this study, we aimed to explore the effect of INK128, a second-generation inhibitor of mTOR, on the inflammatory cytokine production in LPS-stimulated RAW 264.7 cells. Our data showed that INK128 strikingly inhibited the phosphorylation of p70S6K, 4E-BP1 and AKTSer473 in both unstimulated and LPS-stimulated cells. Although it increased the phosphorylation levels of inhibitor kappa-B (IκB) in LPS-stimulated cells, INK128 did not significantly change the levels of NF-κB phosphorylation. In addition, LPS-induced expression of IL-1β and IL-6 was markedly suppressed by INK128 at both mRNA and protein levels. However, the expression of Tumor necrosis factor-alpha (TNF-α protein), but not its mRNA level, was suppressed by this reagent. Our results suggest that the mTOR inhibitor INK128 not only regulates the NF-κB signaling but also influences the inflammatory cytokine expression at both transcriptional and translational levels.
authors.affiliation: Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Ouyang
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Qing-Bin
authors.initials: QB
authors.lastname: Zha
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Hou
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: He
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology*; D001583:Benzoxazoles / Q000276:immunology / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D039642:Eukaryotic Initiation Factors; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000276:immunology / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D001583:Benzoxazoles; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D012333:RNA, Messenger; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C499527:Eif4ebp1 protein, mouse; C587672:IL1B protein, mouse; C498144:Rela protein, mouse; C546843:mTOR protein, mouse; C572449:sapanisertib; D000225:Adenine