title: Cyclo(His-Pro) exerts anti-inflammatory effects by modulating NF-κB and Nrf2 signalling.
abstract: Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts oxidative damage protection by selectively activating the transcription factor Nrf2 signalling pathway. Given the existence of a tight interplay of the Nrf2/NF-κB systems and that the pro-inflammatory response is governed by transcription factor NF-κB, here we sought to investigate whether and how cyclo(His-Pro) interferes with the cross-talk between the antioxidant Nrf2/heme oxygenase-1 and the pro-inflammatory NF-κB pathways. By knocking down the Nrf2 gene, we confirmed that cyclo(His-Pro) inhibits NF-κB nuclear accumulation induced by paraquat in rat pheochromocytoma PC12 cells via the Nrf2/heme oxygenase-1 pathway. The protection required functional heme oxygenase-1 activity, since zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, prevented NF-κB inhibition, and the presence of exogenous carbon monoxide and bilirubin afforded cytoprotection against paraquat-induced toxicity by preventing NF-κB activation. Cyclooxygenase-2 and matrix metalloproteinase 3, two gene products governed by NF-κB, were down-regulated by cyclo(His-Pro) and up-regulated in heme oxygenase-1 knock-down cells. We validated the general mechanism underlying the anti-inflammatory effects by treating PC12 and murine microglial BV2 cells with different pro-inflammatory agents. Finally, cyclo(His-Pro) reduced 12-otetradecanoylphorbol-13-acetate-induced oedema in mouse ear inflammation model. Results, by showing that cyclo(His-pro) suppresses the pro-inflammatory NF-κB signalling via the Nrf2-mediated heme oxygenase-1 activation, contribute to the understanding of essential cellular pathways and allow the proposal of cyclo(His-Pro) as an in vivo anti-inflammatory compound.
authors.affiliation: Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biochimica Cellulare, Università di Perugia, Via del Giochetto, 06123 Perugia, Italy. aminelli@unipg.it
authors.forename: Alba
authors.initials: A
authors.lastname: Minelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Grottelli
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mierla
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellezza
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage* / Q000009:adverse effects; D002248:Carbon Monoxide / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D004487:Edema / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010031:Otitis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018384:Oxidative Stress; D016716:PC12 Cells; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000494:pharmacology*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D010456:Peptides, Cyclic; D010879:Piperazines; D034741:RNA, Small Interfering; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3; C015924:histidyl-proline diketopiperazine