title: PKC412 (CGP41251) modulates the proliferation and lipopolysaccharide-induced inflammatory responses of RAW 264.7 macrophages.
abstract: PKC412 (CGP41251) is a multitarget protein kinase inhibitor with anti-tumor activities. Here, we investigated the effects of PKC412 on macrophages. PKC412 inhibited the proliferation of murine RAW 264.7 macrophages through induction of G2/M cell cycle arrest and apoptosis. At non-toxic drug concentrations, PKC412 significantly suppressed the lipopolysaccharide (LPS)-induced release of TNF-alpha and nitric oxide, while instead enhancing IL-6 secretion. PKC412 attenuated LPS-induced phosphorylations of MKK4 and JNK, as well as AP-1 DNA binding activities. Furthermore, PKC412 suppressed LPS-induced Akt and GSK-3beta phosphorylations. These results suggest that the anti-proliferative and immunomodulatory effects of PKC412 are, at least in part, mediated through its interference with the MKK4/JNK/AP-1 and/or Akt/GSK-3beta pathways. Since macrophages contribute significantly to the development of both acute and chronic inflammation, PKC412 may have therapeutic potential and applications in treating inflammatory and/or autoimmune diseases.
authors.affiliation: Department of Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Miyatake
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Kahoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takaku
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Takata
authors.forename: Shunji
authors.initials: S
authors.lastname: Nakano
authors.forename: Natsuo
authors.initials: N
authors.lastname: Yasui
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D007155:Immunologic Factors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D016207:Cytokines; D004338:Drug Combinations; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D019311:Staurosporine; C059539:midostaurin