TY - JOUR
T1 - Novel modulatory effects of SDZ 62-434 on inflammatory events in activated macrophage-like and monocytic cells
AU - Lee, Ji Yeon
AU - Rhee, Man Hee
AU - Cho, Jae Youl
PY - 2008/4
Y1 - 2008/4
N2 - 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 (β1-integrins) including (1) the production of human and mouse tumor necrosis factor (TNF)-α, (2) the generation of prostaglandin E2 (PGE2), (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 β1-integrin (CD29) assessed by U937 cell-cell adhesion, and (7) the transcriptional up-regulation of inducible NO synthase (iNOS), TNF-α, cyclooxygenase (COX)-2, interleukin (IL)-1β, 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-κB 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-κB inhibitory activity.
AB - 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 (β1-integrins) including (1) the production of human and mouse tumor necrosis factor (TNF)-α, (2) the generation of prostaglandin E2 (PGE2), (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 β1-integrin (CD29) assessed by U937 cell-cell adhesion, and (7) the transcriptional up-regulation of inducible NO synthase (iNOS), TNF-α, cyclooxygenase (COX)-2, interleukin (IL)-1β, 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-κB 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-κB inhibitory activity.
KW - Anti-inflammatory effects
KW - Macrophage-like cells
KW - Monocytic cells
KW - PI3K/Akt pathway
KW - SDZ 62-434
UR - http://www.scopus.com/inward/record.url?scp=41049113062&partnerID=8YFLogxK
U2 - 10.1007/s00210-008-0266-y
DO - 10.1007/s00210-008-0266-y
M3 - Article
C2 - 18299817
AN - SCOPUS:41049113062
SN - 0028-1298
VL - 377
SP - 111
EP - 124
JO - Naunyn-Schmiedeberg's Archives of Pharmacology
JF - Naunyn-Schmiedeberg's Archives of Pharmacology
IS - 2
ER -