title: Intracellular signaling modifications involved in the anti-inflammatory effect of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines on macrophages.
abstract: Inflammation is part of a complex biological response directed by the immune system to fight pathogens and maintain homeostasis. Dysregulation of the inflammatory process leads to development of chronic inflammatory or autoimmune diseases. Several cell types, such as macrophages, and cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) are involved in the regulation of inflammation. The important role played by these cytokines as mediators of the inflammatory process and the side effects of current therapies have promoted the search of new therapeutic alternatives. Quinoxalines are important compounds allowing a wide range of chemical modifications in order to provide an extensive repertoire of biological activities. We have previously shown that a series of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines exhibit potent anti-inflammatory activity, inhibiting the production of TNF-α and IL-6. Our aim here was to study the mechanism thereby this series of compounds act upon different intracellular signaling pathways to uncover their potential molecular targets. By using immunoblotting assays, we found that these compounds inhibit ERK 1/2 and JNK/c-Jun cascades, and reduce c-Fos expression, while activate the anti-inflammatory PI3K/Akt route. These results provide further information on their effect upon the intracellular signal transduction mechanisms leading to inhibition of TNF-α and IL-6 secretion. Our results may be of great interest for the pharmaceutical industry, and could be used as a starting point for the development of new and more potent anti-inflammatory drugs derived from the quinoxaline core.
authors.affiliation: Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, 30100 Murcia, Spain. Electronic address: ajruiz@um.es.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Ruiz-Alcaraz
authors.affiliation: Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, 30100 Murcia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Tristán-Manzano
authors.affiliation: Departamento de Química Orgánica, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Guirado
authors.affiliation: Departamento de Química Física, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gálvez
authors.affiliation: Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, 30100 Murcia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martínez-Esparza
authors.affiliation: Departamento de Bioquímica, Biología Molecular (B) e Inmunología, Facultad de Medicina, IMIB and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, 30100 Murcia, Spain. Electronic address: pigarcia@um.es.
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Peñarrubia
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D011810:Quinoxalines; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases
keywords: Anti-inflammatory therapy; Kinases; Macrophages; Molecular targets; Quinoxalines; Transcription factors