Novel modulatory effects of SDZ 62-434 on inflammatory events in activated macrophage-like and monocytic cells.
In this study, we investigated the novel pharmacological activity of SDZ 62-434 on various inflammatory events mediated by monocytes/macrophages (peritoneal macrophages and U937/RAW 264.7 cells) and its putative mechanism of action. SDZ 62-434 strongly inhibited various inflammatory responses induced by lipopolysaccharide (LPS) or function-activating antibody to CD29 (beta1-integrins) including (1) the production of human and mouse tumor necrosis factor (TNF)-alpha, (2) the generation of prostaglandin E(2) (PGE(2)), (3) the release of nitric oxide (NO) and reactive oxygen species (ROS), (4) the increased level of phagocytic uptake, (5) the up-regulation of surface costimulatory molecules CD80, CD86, and CD40, (6) functional activation of beta1-integrin (CD29) assessed by U937 cell-cell adhesion, and (7) the transcriptional up-regulation of inducible NO synthase (iNOS), TNF-alpha, cyclooxygenase (COX)-2, interleukin (IL)-1beta, and IL-6. The anti-inflammatory effects of SDZ 62-434 seem to be mediated by interrupting the early-activated intracellular signaling cascades composed of phosphoinositide 3-kinase (PI3K)/Akt and NF-kappaB but not Janus kinase-2 (JAK-2), extracellular signal-regulated kinase (ERK), p38, or C-Jun N-terminal kinase (JNK), according to pharmacological, biochemical and functional analyses. Therefore, these results suggest that SDZ 62-434 may have anti-inflammatory features derived from PI3K/Akt/NF-kappaB inhibitory activity.
Lee
Ji Yeon
JY
School of Bioscience and Biotechnology, and Institute of Bioscience and Biotechnology, Kangwon National University, 192-1 Hyoja-2-Dong, Chuncheon 200-701, South Korea.
Rhee
Man Hee
MH
Cho
Jae Youl
JY
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007093:Imidazoles; D007546:Isoquinolines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C081240:SDZ 62-434; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone