Abstract
Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E2, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-κB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway.
Highlights
Inflammation is a crucial defense mechanism against pathogens and various external stimuli [1].Macrophages play an important role in inflammatory and other immune processes
We first evaluated the inhibitory effects of phorbaketal A (Figure 1A), isolated from the marine sponge Phorbas sp., on the production of two key inflammatory mediators, nitric oxide (NO) and prostaglandin E2 (PGE2), in macrophages
We investigated whether the inhibitory effects of phorbaketal A on NO production were associated with regulation of the expression of inducible NO synthase
Summary
Inflammation is a crucial defense mechanism against pathogens and various external stimuli [1]. When macrophages are activated by external stimuli, they produce and secrete numerous endogenous inflammatory mediators, including prostaglandin E2 (PGE2), nitric oxide (NO), and pro-inflammatory cytokines [2]. These pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1beta (1β), IL-6, and monocyte chemotactic protein-1 (MCP-1), have pleiotropic effects on immune responses and acute-phase reactions [3]. In activated macrophages, HO-1 and its products have been shown to exert anti-inflammatory effects via attenuation of the expression of pro-inflammatory mediators such as NO, PGE2, TNF-α, IL-1β, IL-6, and MCP-1 [10,11,12,13]. In this study, we investigated the anti-inflammatory activities of phorbaketal A and its molecular mechanism in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages
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