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.

Castorina, A; Scheller, J; Keay, KA; Marzagalli, R; Rose-John, S; Campbell, IL

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.

Castorina, A

Scheller, J Keay, KA Marzagalli, R Rose-John, S Campbell, IL

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Publisher:: MDPI
Publication Type:: Journal Article
Citation:: Int J Mol Sci, 2024, 25, (17), pp. 9453
Issue Date:: 2024-08-30

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Field	Value	Language
dc.contributor.author	Castorina, A https://orcid.org/0000-0001-7037-759X
dc.contributor.author	Scheller, J
dc.contributor.author	Keay, KA
dc.contributor.author	Marzagalli, R
dc.contributor.author	Rose-John, S
dc.contributor.author	Campbell, IL
dc.date.accessioned	2024-12-02T00:52:24Z
dc.date.available	2024-08-29
dc.date.available	2024-12-02T00:52:24Z
dc.date.issued	2024-08-30
dc.identifier.citation	Int J Mol Sci, 2024, 25, (17), pp. 9453
dc.identifier.issn	1422-0067
dc.identifier.issn	1422-0067
dc.identifier.uri	http://hdl.handle.net/10453/182178
dc.description.abstract	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-κB 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-κB 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.
dc.format	Electronic
dc.language	eng
dc.publisher	MDPI
dc.relation.ispartof	Int J Mol Sci
dc.relation.isbasedon	10.3390/ijms25179453
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences
dc.subject.classification	Chemical Physics
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3107 Microbiology
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.mesh	Animals
dc.subject.mesh	Pituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.mesh	Interleukin-6
dc.subject.mesh	Mice
dc.subject.mesh	Vasoactive Intestinal Peptide
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Brain
dc.subject.mesh	Astrocytes
dc.subject.mesh	Humans
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Glial Fibrillary Acidic Protein
dc.subject.mesh	Central Nervous System
dc.subject.mesh	STAT3 Transcription Factor
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Central Nervous System
dc.subject.mesh	Brain
dc.subject.mesh	Astrocytes
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Glial Fibrillary Acidic Protein
dc.subject.mesh	Vasoactive Intestinal Peptide
dc.subject.mesh	Interleukin-6
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Male
dc.subject.mesh	STAT3 Transcription Factor
dc.subject.mesh	Pituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.mesh	Animals
dc.subject.mesh	Pituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.mesh	Interleukin-6
dc.subject.mesh	Mice
dc.subject.mesh	Vasoactive Intestinal Peptide
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Brain
dc.subject.mesh	Astrocytes
dc.subject.mesh	Humans
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Glial Fibrillary Acidic Protein
dc.subject.mesh	Central Nervous System
dc.subject.mesh	STAT3 Transcription Factor
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.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.
dc.type	Journal Article
utslib.citation.volume	25
utslib.location.activity	Switzerland
utslib.for	0399 Other Chemical Sciences
utslib.for	0604 Genetics
utslib.for	0699 Other Biological Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-12-02T00:52:15Z
pubs.issue	17
pubs.publication-status	Published online
pubs.volume	25
utslib.citation.issue	17

Abstract:

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-κB 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-κB 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.

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http://hdl.handle.net/10453/182178