Abstract
Aim:
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 PGE2 in LPS-activated RAW264.7 cells and peritoneal macrophages (the IC50 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.
Conclusion:
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR . Macrophages in rheumatoid arthritis. Arthritis Res 2000; 2: 189–202.
Owens T, Babcock AA, Millward JM, Toft-Hansen H . Cytokine and chemokine inter-regulation in the inflamed or injured CNS. Brain Res Brain Res Rev 2005; 48: 178–84.
Eizirik DL, Colli ML, Ortis F . The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 2009; 5: 219–26.
Brown KD, Claudio E, Siebenlist U . The roles of the classical and alternative nuclear factor-kappa B pathways: potential implications for autoimmunity and rheumatoid arthritis. Arthritis Res Ther 2008; 10: 212.
Grieco FA, Vendrame F, Spagnuolo I, Dotta F . Innate immunity and the pathogenesis of type 1 diabetes. Semin Immunopathol 2011; 33: 57–66.
Tsan MF, Gao B . Endogenous ligands of Toll-like receptors. J Leukoc Biol 2004; 76: 514–9.
Mendes Sdos S, Candi A, Vansteenbrugge M, Pignon MR, Bult H, Boudjeltia KZ, et al. Microarray analyses of the effects of NF-kappaB or PI3K pathway inhibitors on the LPS-induced gene expression profile in RAW264.7 cells: synergistic effects of rapamycin on LPS-induced MMP9-overexpression. Cell Signal 2009; 21: 1109–22.
Min KJ, Lee JT, Joe EH, Kwon TK . An IkappaBalpha phosphorylation inhibitor induces heme oxygenase-1 (HO-1) expression through the activation of reactive oxygen species (ROS)-Nrf2-ARE signaling and ROS-PI3K/Akt signaling in an NF-kappaB-independent mechanism. Cell Signal 2011; 23: 1505–13.
Lee H, Lin CI, Liao JJ, Lee YW, Yang HY, Lee CY, et al. Lysophospholipids increase ICAM-1 expression in HUVEC through a Gi- and NF-kappaB-dependent mechanism. Am J Physiol Cell Physiol 2004; 287: C1657–66.
Dai Y, Rahmani M, Grant S . Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 2003; 22: 7108–22.
Pierce JW, Schoenleber R, Jesmok G, Best J, Moore SA, Collins T, et al. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem 1997; 272: 21096–103.
Yu T, Ahn HM, Shen T, Yoon K, Jang HJ, Lee YJ, et al. Anti-inflammatory activity of ethanol extract derived from Phaseolus angularis beans. J Ethnopharmacol 2011; 137: 1197–206.
Yu T, Lee YJ, Jang HJ, Kim AR, Hong S, Kim TW, et al. Anti-inflammatory activity of Sorbus commixta water extract and its molecular inhibitory mechanism. J Ethnopharmacol 2011; 134: 493–500.
Pyo S . The mechanism of poly I:C-induced antiviral activity in peritoneal macrophage. Arch Pharm Res 1994; 17: 93–9.
Jang SA, Kang SC, Sohn EH . Phagocytic effects of beta-glucans from the mushroom coriolus versicolor are related to Dectin-1, NOS, TNF-alpha signaling in macrophages. Biomol Ther 2011; 19: 438–44.
Cho JY, Baik KU, Jung JH . Park MH . In vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone, from Saussurea lappa. Eur J Pharmacol 2000; 398: 399–407.
Kang TJ, Moon JS, Lee S, Yirn D . Polyacetylene compound from Cirsium japonicum var ussuriense inhibits the LPS-Induced inflammatory reaction via suppression of NF-kappa B activity in RAW 264.7 cells. Biomol Ther 2011; 19: 97–101.
Jung YH, Park KY, Jeon JH, Kwak YS, Song YB, Wee JJ, et al. Red ginseng saponin fraction A isolated from Korean red ginseng by ultrafiltration on the porcine coronary artery. J Ginseng Res 2011; 35: 325–30.
Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, et al. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 1988; 20: 309–21.
Kim JR, Oh DR, Cha MH, Pyo BS, Rhee JH, Choy HE, et al. Protective effect of polygoni cuspidati radix and emodin on Vibrio vulnificus cytotoxicity and infection. J Microbiol 2008; 46: 737–43.
Kim YJ, Lee JH, Lee OR, Shim JS, Jung SK, Son NR, et al. Isolation and characterization of a type II peroxiredoxin gene from Panax ginseng C. A. Meyer. J Ginseng Res 2010; 34: 296–303.
Jin M, Park S, Pyo MY . Suppressive effects of T-412, a flavone on interleukin-4 production in T cells. Biol Pharm Bull 2009; 32: 1875–9.
Jung KK, Lee HS, Cho JY, Shin WC, Rhee MH, Kim TG, et al. Inhibitory effect of curcumin on nitric oxide production from lipopolysaccharide-activated primary microglia. Life Sci 2006; 79: 2022–31.
Shen T, Lee J, Park MH, Lee YG, Rho HS, Kwak YS, et al. Ginsenoside Rp(1), a ginsenoside derivative, blocks promoter activation of iNOS and COX-2 genes by suppression of an IKK beta-mediated NF-kappa B pathway in HEK293 cells. J Ginseng Res 2011; 35: 200–8.
Byeon SE, Lee YG, Kim BH, Shen T, Lee SY, Park HJ, et al. Surfactin blocks NO production in lipopolysaccharide-activated macrophages by inhibiting NF-kappaB activation. J Microbiol Biotechnol 2008; 18: 1984–9.
Sohn EH, Jang SA, Lee CH, Jang KH, Kang SC, Park HJ, et al. Effects of Korean red ginseng extract for the treatment of atopic dermatitis-like skin lesions in mice. J Ginseng Res 2011; 35: 479–86.
Okabe S, Miyake H, Awane Y . Cytoprotective effects of NC-1300 and omeprazole on HCl. ethanol-induced gastric lesions in rats. Jpn J Pharmacol 1986; 42: 123–33.
Cho JY, Yeon JD, Kim JY, Yoo ES, Yu YH, Park MH . Hepatoprotection by human epidermal growth factor (hEGF) against experimental hepatitis induced by D-galactosamine (D-galN) or D-GalN/lipopolysaccharide. Biol Pharm Bull 2000; 23: 1243–6.
Lee YG, Chain BM, Cho JY . Distinct role of spleen tyrosine kinase in the early phosphorylation of inhibitor of kappaB alpha via activation of the phosphoinositide-3-kinase and Akt pathways. Int J Biochem Cell Biol 2009; 41: 811–21.
Lee YG, Lee J, Byeon SE, Yoo DS, Kim MH, Lee SY, et al. Functional role of Akt in macrophage-mediated innate immunity. Front Biosci 2011; 16: 517–30.
Jung CH, Jung H, Shin YC, Park JH, Jun CY, Kim HM, et al. Eleutherococcus senticosus extract attenuates LPS-induced iNOS expression through the inhibition of Akt and JNK pathways in murine macrophage. J Ethnopharmacol 2007; 113: 183–7.
Park SY, Park GY, Ko WS, Kim Y . Dichroa febrifuga Lour inhibits the production of IL-1beta and IL-6 through blocking NF-kappaB, MAPK and Akt activation in macrophages. J Ethnopharmacol 2009; 125: 246–51.
Francisco V, Figueirinha A, Neves BM, Garcia-Rodriguez C, Lopes MC, Cruz MT, et al. Cymbopogon citratus as source of new and safe anti-inflammatory drugs: bio-guided assay using lipopolysaccharide-stimulated macrophages. J Ethnopharmacol 2011; 133: 818–27.
Poolman TM, Ng LL, Farmer PB, Manson MM . Inhibition of the respiratory burst by resveratrol in human monocytes: correlation with inhibition of PI3K signaling. Free Radic Biol Med 2005; 39: 118–32.
Larmonier CB, Midura-Kiela MT, Ramalingam R, Laubitz D, Janikashvili N, Larmonier N, et al. Modulation of neutrophil motility by curcumin: implications for inflammatory bowel disease. Inflamm Bowel Dis 2011; 17: 503–15.
Ruiz PA, Braune A, Holzlwimmer G, Quintanilla-Fend L, Haller D . Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr 2007; 137: 1208–15.
Byeon SE, Chung JY, Lee YG, Kim BH, Kim KH, Cho JY . In vitro and in vivo anti-inflammatory effects of taheebo, a water extract from the inner bark of Tabebuia avellanedae. J Ethnopharmacol 2008; 119: 145–52.
Acknowledgements
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (to Jae Youl CHO) (No 2011-0016397).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jung, Y., Byeon, S., Yoo, D. et al. 8-(Tosylamino)quinoline inhibits macrophage-mediated inflammation by suppressing NF-κB signaling. Acta Pharmacol Sin 33, 1037–1046 (2012). https://doi.org/10.1038/aps.2012.52
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2012.52
Keywords
This article is cited by
-
Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response
Acta Pharmacologica Sinica (2014)
-
Synthesis and further rearrangements of 7-(2-cycloalken-1-yl)-8-quinolinols
Monatshefte für Chemie - Chemical Monthly (2014)
