The role of PKC/ERK1/2 signaling in the anti-inflammatory effect of tetracyclic triterpene euphol on TPA-induced skin inflammation in mice

Abstract

Inflammation underlies the development and progression of a number of skin disorders including psoriasis, atopic dermatitis and cancer. Therefore, novel antiinflammatory agents are of great clinical interest for prevention and treatment of these conditions. Herein, we demonstrated the underlying molecular mechanisms of the antiinflammatory activity of euphol, a tetracyclic triterpene isolated from the sap of Euphorbia tirucalli, in skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. Topical application of euphol (100 μg/ear) significantly inhibited TPA-induced ear edema and leukocyte influx through the reduction of keratinocyte-derived chemokine (CXCL1/KC) and macrophage inflammatory protein (MIP)-2 levels. At the intracellular level, euphol reduced TPA-induced extracellular signal-regulated protein kinase (ERK) activation and cyclooxygenase-2 (COX-2) upregulation. These effects were associated with euphol's ability to prevent TPA-induced protein kinase C (PKC) activation, namely PKCα and PKCδ isozymes. Our data indicate that topical application of euphol markedly inhibits the inflammatory response induced by TPA. Thus, euphol represents a promising agent for the management of skin diseases with an inflammatory component.

Potent Anti-inflammatory and Analgesic Actions of the Chloroform Extract of <i>Dendropanax morbifera</i> Mediated by the Nrf2/HO-1 Pathway

“…In this model, the inflammation is induced by complex processes including activation of intracellular pathways such as MAPKs and NF-κB, the release of inflammatory mediators and cytokines, and the infiltration of neutrophils and macrophages. 48,49) Of note, inflammatory reactions both in keratinocytes and in infiltrated immune cells including macrophages play important roles in induction of ear edema. We examined if DP-C modulates inflammatory reaction in keratinocytes stimulated by combination of IFN-γ and TNF-α, but DP-C failed to show inhibitory effect of NO release in keratinocyte with the same concentration tested in the macrophages (Supplementary Fig.…”

Euphol arrests breast cancer cells at the G1 phase through the modulation of cyclin D1, p21 and p27 expression

“…The anti-inflammatory effects of euphol have been demonstrated to be associated with the inhibition of the activation of nuclear factor-κB (14), downregulation of tumor necrosis factor-α and cyclooxygenase-2 (15), inhibition of the T cell-mediated immune response (15), and the reduction of protein kinase C/extracellular signal-regulated protein kinase signaling activation (16). In addition to the antiviral and anti-inflammatory effects, the antitumor effects of euphol have also been observed.…”

Euphorbia Kansui Reactivates Latent HIV

“…Euphorbia kansui contains 12 ingenols, as well as sesquiterpenoids, triterpenoids, and euphols [37–39]. This combination of active compounds could contribute to the observed reactivation of latent HIV, and the reported anti-inflammatory properties of euphols [47,48] may mitigate the adverse inflammatory effects of ingenols in Euphorbia kansui. The efficacy of Euphorbia kansui is equivalent to that of the purified IngDB, and a titration of Euphorbia kansui in 2D10 cells demonstrated dose-dependent responses of T cell activation and HIV reactivation.…”

“…Euphorbia kansui, as an unpurified preparation, has been used in traditional Chinese medicine for thousands of years [43], and Aveloz, or Euphorbia tirucalli, has been used in Brazil to treat cancer [41]. Euphol, another bioactive component of Euphorbia Euphorbia kansui has anti-inflammatory properties [47,48]. The natural combination ingenols and euphols in Euphorbia kansui may prove a safer therapeutic approach than treatment with purified ingenol alone, as the anti-inflammatory properties of the euphol potentially reduce the inflammatory side-effects of the ingenols.…”