title: Curcumin induces differential expression of cytoprotective enzymes but similar apoptotic responses in fibroblasts and myofibroblasts.
abstract: Excessive extracellular matrix (ECM) deposition and tissue contraction after injury can lead to esthetic and functional problems. Fibroblasts and myofibroblasts activated by transforming growth factor (TGF)-β1 play a key role in these processes. The persistence of (myo)fibroblasts and their excessive ECM production and continuous wound contraction have been linked to pathological scarring. The identification of compounds reducing myofibroblast survival and function may thus offer promising therapeutic strategies to optimize impaired wound healing. The plant-derived polyphenol curcumin has shown promising results as a wound healing therapeutic in vivo; however, the exact mechanism is still unclear. In vitro, curcumin induces apoptosis in various cell types via a reactive oxygen species (ROS)-dependent mechanism. Here we treated human dermal fibroblasts with TGF-β1 to induce myofibroblast differentiation, and compared the responses of fibroblasts and myofibroblasts to 25 µM curcumin. Curcumin induced caspase-independent apoptosis in both fibroblasts and myofibroblasts in a ROS-dependent manner. Oxidative stress leads to the induction of several antioxidant systems to regain cellular homeostasis. We detected stress-induced induction of heme oxygenase (HO)-1 in fibroblasts but not in myofibroblasts following curcumin exposure. Instead, myofibroblasts expressed higher levels of heat shock protein (HSP)72 compared to fibroblasts in response to curcumin, suggesting that TGF-β1 treatment alters the stress-responses of the cells. However, we did not detect any differences in curcumin toxicity between the two populations. The differential stress responses in fibroblasts and myofibroblasts may open new therapeutic approaches to reduce myofibroblasts and scarring.
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Ditte M S
authors.initials: DMS
authors.lastname: Lundvig
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Sebastiaan W C
authors.initials: SWC
authors.lastname: Pennings
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Katrien M
authors.initials: KM
authors.lastname: Brouwer
authors.affiliation: Department of Orthodontics, Paedodontics and Community Dentistry, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
authors.forename: Matilda
authors.initials: M
authors.lastname: Mtaya-Mlangwa
authors.affiliation: Department of Orthodontics, Paedodontics and Community Dentistry, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
authors.forename: Emeria A
authors.initials: EA
authors.lastname: Mugonzibwa
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Kuijpers-Jagtman
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Von den Hoff
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Frank.wagener@radboudumc.nl.
authors.forename: Frank A D T G
authors.initials: FADTG
authors.lastname: Wagener
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000096:biosynthesis; D053179:Caspase 7 / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D019610:Cytoprotection; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D058628:Myofibroblasts / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D050884:HSP72 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D051547:Heme Oxygenase-1; D053148:Caspase 3; D053179:Caspase 7; D003474:Curcumin
keywords: Curcumin; Fibroblasts; Heat shock proteins; Heme oxygenase; Myofibroblasts; Scarring