Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia
Abstract
The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of proinflammatory factors. In the present study the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway and on the subsequent changes in Jun family members, a transduction pathway clearly involved in the activation of microglia cells were examined. VIP/PACAP inhibit MEKK1 activity and the subsequent phosphorylations of MEK4, JNK, and c-Jun, which result in a decrease in the AP-1 binding and a marked change in the composition of AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Furthermore, VIP stimulates JunB production in LPS-stimulated microglia. Both inhibition of the MEKK1/MEK4/JNK pathway, leading to a reduction in phosphorylated c-Jun, and the stimulation of JunB are mediated through the specific VPAC1 receptor and cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides.
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In microglia, LPS treatment results in activation of MAP3K1, which is an upstream activator of IKK.
“Specifically, in microglia, LPS treatment results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1, also known as MEKK1), which is an upstream activator of IKK [148].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [148]
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- Authors
- Delgado, M.
- Affiliations
- Universidad Complutense de Madrid (ES)
- Corresponding author
- Delgado, Mario
- ORCID
- Delgado, Mario
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 293
- Issue
- 2
- Pages
- 771-776
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2138835395
- Cited by
- 53
- References
- 29
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 6 · 2021: 1 · 2020: 2 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 4 · 2012: 2
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, microglial activation, endotoxin, lipopolysaccharide, JunB, c-Jun, AP-1, VPAC1 receptor, cAMP/PKA signaling, neuroinflammation, anti-inflammatory neuropeptides
- MeSH terms
- Cyclic AMP, Animals, Cells, Cultured, Enzyme Inhibitors, Kinetics, Lipopolysaccharides, Macrophages, Neuropeptides, Vasoactive Intestinal Peptide, Proto-Oncogene Proteins c-jun, Protein Serine-Threonine Kinases, Microglia, Receptors, Vasoactive Intestinal Peptide, Transcription Factor AP-1, Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 4, Pituitary Adenylate Cyclase-Activating Polypeptide, Receptors, Vasoactive Intestinal Polypeptide, Type I
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