{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:56:55Z","timestamp":1791644215191,"version":"4.3.4"},"reference-count":66,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"International Research Collaborative Award (IRCA 2014) from The University of Sydney"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative\/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP\/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6\/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP\/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK\/STAT3, NF-\u03baB and ERK1\/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6\/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-\u03baB pathways, but it failed to rescue PACAP, PACAP\/VIP receptors and Erk1\/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP\/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP\/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences.<\/jats:p>","DOI":"10.3390\/ijms25179453","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T09:39:32Z","timestamp":1725010772000},"page":"9453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Increased Expression of the Neuropeptides PACAP\/VIP in the Brain of Mice with CNS Targeted Production of IL-6 Is Mediated in Part by Trans-Signalling"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7037-759X","authenticated-orcid":false,"given":"Alessandro","family":"Castorina","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurgen","family":"Scheller","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3934-4380","authenticated-orcid":false,"given":"Kevin A.","family":"Keay","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubina","family":"Marzagalli","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7519-3279","authenticated-orcid":false,"given":"Stefan","family":"Rose-John","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8681-1100","authenticated-orcid":false,"given":"Iain L.","family":"Campbell","sequence":"additional","affiliation":[{"name":"School of Molecular Bioscience, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrn2054","article-title":"The neuropoietic cytokine family in development, plasticity, disease and injury","volume":"8","author":"Bauer","year":"2007","journal-title":"Nat. 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