8-(Tosylamino)quinoline inhibits macrophage-mediated inflammation by suppressing NF-κB signaling.
OBJECTIVE
The macrophage-mediated inflammatory response may contribute to the development of cancer, diabetes, atherosclerosis and septic shock. This study was to characterize several new compounds to suppress macrophage-mediated inflammation.


METHODS
Peritoneal macrophages from C57BL/6 male mice and RAW264.7 cells were examined. Anti-inflammatory activity was evaluated in the cells exposed to lipopolysaccharide (LPS). The mechanisms of the anti-inflammatory activity were investigated via measuring transcription factor activation in response to specific signals and via assaying the activities of the target kinases.


RESULTS
Of 7 candidate compounds tested, 8-(tosylamino)quinoline (8-TQ, compound 7) exhibited the strongest activities in suppressing the production of NO, TNF-α, and PGE(2) in LPS-activated RAW264.7 cells and peritoneal macrophages (the IC(50) values=1-5 μmol/L). This compound (1.25-20 μmol/L) dose-dependently suppressed the expression of the pro-inflammatory genes for iNOS, COX-2, TNF-α, and the cytokines IL-1β and IL-6 at the level of transcription in LPS-activated RAW264.7 cells. 8-TQ (20 μmol/L) significantly suppressed the activation of NF-κB and its upstream signaling elements, including inhibitor of κB (IκBα), IκBα kinase (IKK) and Akt in LPS-activated RAW264.7 cells. In in vivo experiments, oral administration of 20 and 40 mg/kg 8-TQ for 3 d significantly alleviated the signs of LPS-induced hepatitis and HCl/EtOH-induced gastritis, respectively, in ICR mice.


CONCLUSIONS
8-TQ (compound 7) exerts significant anti-inflammatory activity through the inhibition of the Akt/NF-κB pathway, thus may be developed as a novel anti-inflammatory drug.
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Yongwoo
Y
Jung
Se Eun
SE
Byeon
Dae Sung
DS
Yoo
Yong Gyu
YG
Lee
Tao
T
Yu
Yanyan
Y
Yang
Ji Hye
JH
Kim
Eunji
E
Kim
Deok
D
Jeong
Man Hee
MH
Rhee
Eui Su
ES
Choung
Sungyoul
S
Hong
Jae Youl
JY
Cho
D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014105:Tosyl Compounds / Q000494:pharmacology*
C579515:8-(tosylamino)quinoline; D018836:Inflammation Mediators; D016328:NF-kappa B; D011804:Quinolines; D014105:Tosyl Compounds