title: 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.
authors.affiliation: Experimental Immunology Laboratory, IDI-IRCCS, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scarponi
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Butturini
authors.affiliation: Experimental Immunology Laboratory, IDI-IRCCS, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Sestito
authors.affiliation: Experimental Immunology Laboratory, IDI-IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Madonna
authors.affiliation: Experimental Immunology Laboratory, IDI-IRCCS, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavani
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Mariotto
authors.affiliation: Experimental Immunology Laboratory, IDI-IRCCS, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Albanesi
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D012717:Sesquiterpenes / Q000494:pharmacology*; D000097043:Interleukin-22
chemical_list: D000893:Anti-Inflammatory Agents; D066246:ErbB Receptors; D005978:Glutathione; D007371:Interferon-gamma; D007378:Interleukins; D007783:Lactones; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; D000097043:Interleukin-22; C083030:dehydrocostus lactone; C002602:costunolide