A new anthranilic acid derivative (1) was isolated from a Philippine sponge, Oscarella stillans (family Plakinidae. phylum Porifera, class Demospongiae, order Homosclerophorida) [1]. The structure of compound 1, designated oscarellin, was determined as 2-amino-3-(3′-aminopropoxy)benzoic acid from spectral data, and confirmed by synthesis. We examined the immunomodulating effect of compound 1 and its mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. LPSs, a bacterial endotoxin, induce the production of inflammatory mediators such as iNOS, COX-2, TNF-α, IL-1, and IL-6 in macrophages [2]. Our data indicated that the expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were significantly reduced by the pretreatment of compound 1 (0.1–10 μM) for 2 h. In addition, oscarellin (1) suppressed activation of c-Jun NH2-termimal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38 mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW 264.7 cells. Compound 1 abrogated LPS-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activities, whereas the induction of activating transcription factor-3 (ATF-3) was increased. Taken together, our results suggest that oscarellin (1) attenuates pro-inflammatory cytokines through the inhibition of JNK, ERK, AP-1, NF-κB and the activation of ATF-3 signaling pathway. In conclusion, the present data suggest that oscarellin (1) is a potential therapeutic agent to treat inflammatory-related diseases.
Acknowledgements: This work was supported by a grant from Marine Biotechnology Program (PJT200620, Genome Analysis of Marine Organisms and Development of Functional Applications) funded by Ministry of Oceans and Fisheries.
References:
[1] Bergquist PR, Kelly M. Taxonomy of some Halisarcida and Homosclerophorida (Porifera: Demospongiae) from the Indo-Pacific. New Zeal J Mar Fresh 2004; 38: 51–66
[2] Hinz B, Brune K. Cyclooxygenase-2 – 10 years later. J Pharmacol Exp Ther 2002; 300: 367–375