Topical application of marine briarane-type diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and dermatitis in murine skin

Abstract

BackgroundSkin is the largest organ in the body, and is directly exposed to extrinsic assaults. As such, the skin plays a central role in host defense and the cutaneous immune system is able to elicit specific local inflammatory and systemic immune responses against harmful stimuli. 12-O-tetradecanoylphorbol-13-acetate (TPA) can stimulate acute and chronic inflammation and tumor promotion in skin. TPA-induced dermatitis is thus a useful in vivo pharmacological platform for drug discovery. In this study, the inhibitory effect of briarane-type diterpenes (BrDs) from marine coral Briareum excavatum on TPA-induced dermatitis and dendritic cell (DC) function was explored.MethodsEvans blue dye exudation was used to determine vascular permeability. H&E-stained skin section was used to determine the formation of edema in mouse abdominal skin. We also used immunohistochemistry staining and western blot assays to evaluate the activation of specific inflammation makers and key mediators of signaling pathway in the mouse skin. Furthermore, mouse bone marrow DCs were used to determine the relationship between the chemical structure of BrDs and their regulation of DC function.ResultsBrD1 remarkably suppressed TPA-induced vascular permeability and edema in skin. At the biochemical level, BrD1 inhibited TPA-induced expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase-9, the key indicators of cutaneous inflammation. This inhibition was apparently mediated by interference with the Akt/NF-κB-mediated signaling network. BrD1 also inhibited TNF-α and IL-6 expression in LPS-stimulated BMDCs. The 8, 17-epoxide of BrDs played a crucial role in the inhibition of IL-6 expression, and replacement of the C-12 hydroxyl group with longer esters in BrDs gradually decreased this inhibitory activity.ConclusionsOur results suggest that BrDs warrant further investigation as natural immunomodulatory agents for control of inflammatory skin diseases.

Anti-Inflammatory and Analgesic Effects of the Marine-Derived Compound Excavatolide B Isolated from the Culture-Type Formosan Gorgonian Briareum excavatum

“…Recent reports have indicated that some marine briarane-type diterpenes from soft coral also have anti-inflammatory potential in LPS-induced macrophages [ 10 , 11 ] or peptide (FMLP/CB)-induced human neutrophil cell models [ 39 , 40 , 41 ]. Moreover, Wei et al has indicated that excavatolide B can reduce the expression of the pro-inflammatory cytokines IL-6 and TNF-α in an LPS-stimulated mouse bone marrow-derived dendritic cell model [ 32 ]. Our present results reveal that both iNOS and COX-2 mRNA expressions are inhibited in the LPS-induced murine macrophage model by excavatolide B.…”

“…iNOS-selective inhibitors inhibit carrageenan-induced nociceptive behavior [ 43 ]. The previous study indicated that excavatolide B could reduce the vascular permeability and iNOS protein expression in TPA-induced skin inflammation [ 32 ]. In the present study, we also demonstrated that excavatolide B could dose-dependently inhibit iNOS gene and protein expression in in vitro and in vivo inflammatory models, respectively.…”

“…The briarane-type diterpene excavatolide B was first isolated from Briareum excavatum by Sheu et al (1998) and shown to have a low cytotoxicity [ 31 ]. Wei et al (2011) found that excavatolide B significantly attenuated 12- O -tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mice [ 32 ]. The carrageenan-injected paw in rat is a well-established animal model of inflammation for the evaluation of anti-inflammatory and analgesic compounds [ 29 , 30 , 33 ].…”

Topical atorvastatin ameliorates 12-O-tetradecanoylphorbol-13-acetate induced skin inflammation by reducing cutaneous cytokine levels and NF-κB activation

“…Skin serves as the first line of defense against microbial pathogens as well as physical and chemical stress or insults (Wei et al 2011). The immune and inflammatory system plays an important role in skin diseases like psoriasis, atopic dermatitis and cancer (Johnson-Huang et al 2009).…”

Inhibiting MDSC differentiation from bone marrow with phytochemical polyacetylenes drastically impairs tumor metastasis

“…BALB/c mouse bone marrow cells from femora and tibiae were depleted of RBCs with ACK lysis buffer and cultured in RPMI 1640 medium supplemented with 20 ng/ml GM-CSF, 10% fetal bovine serum, 50 μM 2-mercaptoethanol, 100 unit/ml penicillin and 100 μg/ml streptomycin in a humidified 5% CO 2 incubator at 37 °C49.…”