Inhibition of Inflammatory and Proliferative Responses of Human Keratinocytes Exposed to the Sesquiterpene Lactones Dehydrocostuslactone and Costunolide

Abstract

The imbalance of the intracellular redox state and, in particular, of the glutathione (GSH)/GSH disulfide couple homeostasis, is involved in the pathogenesis of a number of diseases. In many skin diseases, including psoriasis, oxidative stress plays an important role, as demonstrated by the observation that treatments leading to increase of the local levels of oxidant species ameliorate the disease. Recently, dehydrocostuslactone (DCE) and costunolide (CS), two terpenes naturally occurring in many plants, have been found to exert various anti-inflammatory and pro-apoptotic effects on different human cell types. These compounds decrease the level of the intracellular GSH by direct interaction with it, and, therefore, can alter cellular redox state. DCE and CS can trigger S-glutathionylation of various substrates, including the transcription factor STAT3 and JAK1/2 proteins. In the present study, we investigated on the potential role of DCE and CS in regulating inflammatory and proliferative responses of human keratinocytes to cytokines. We demonstrated that DCE and CS decreased intracellular GSH levels in human keratinocytes, as well as inhibited STAT3 and STAT1 phosphorylation and activation triggered by IL-22 or IFN-γ, respectively. Consequently, DCE and CS decreased the IL-22- and IFN-γ-induced expression of inflammatory and regulatory genes in keratinocytes, including CCL2, CXCL10, ICAM-1 and SOCS3. DCE and CS also inhibited proliferation and cell-cycle progression-related gene expression, as well as they promoted cell cycle arrest and apoptosis. In parallel, DCE and CS activated the anti-inflammatory EGFR and ERK1/2 molecules in keratinocytes, and, thus, wound healing in an in vitro injury model. In light of our findings, we can hypothesize that the employment of DCE and CS in psoriasis could efficiently counteract the pro-inflammatory effects of IFN-γ and IL-22 on keratinocytes, revert the apoptosis-resistant phenotype, as well as inhibit hyperproliferation in the psoriatic epidermis.

IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment

“…Normal human keratinocytes were established from sun-protected skin of healthy individuals ( n = 4) and cultured as previously reported 47 . Cells were plated at 5000/cm 2 and maintained to 4-d post confluency.…”

CXCL10 in psoriasis

“…As a consequence, CS and DCE reduced the 306 IL-22-and IFN-g-induced expression of inflammatory and 307 regulatory genes in keratinocytes, including CCL2 and CXCL10. It 308 was hypothesized that using CS and DCE in PsO therapy the pro-309 inflammatory actions of IFN-g and IL-22 on keratinocytes may be 310 reduced [92].…”

Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2

“…Costunolide (C 15 H 20 O 2 ) is a well-studied natural product that exhibits a broad range of biological activities, including anti-oxidant, anti-inflammatory and anti-tumor effects [7][8][9][10][11]. Interestingly, recent studies demonstrated that costunolide had potent hepatic protective effects.…”