Diacylglycerol kinase synthesized by commensal Lactobacillus reuteri diminishes Protein Kinase C phosphorylation and histamine-mediated signaling in the mammalian intestinal epithelium

Autor: Magdalena Esparza, Mark T. Whary, Anthony M. Haag, J. W. Nelson, Robert Fultz, Susan Venable, Anne Hall, James G. Fox, James Versalovic, M. Lugo, Sriram Ayyaswamy, Bhanu P. Ganesh
Přispěvatelé: Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Mathematics, Massachusetts Institute of Technology. Department of Mechanical Engineering, Massachusetts Institute of Technology. Division of Comparative Medicine, Massachusetts Institute of Technology. Institute for Data, Systems, and Society, MIT Energy Initiative, Hall, Alexandra E., Nelson, Jordan William, Esparza, Marcos A., Lugo, Michael T, Whary, Mark T, Fox, James G, Versalovic, James
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Limosilactobacillus reuteri
H1R
Mitogen-activated protein kinase kinase
MAP2K7
Histamine receptor
Mice
0302 clinical medicine
Immunology and Allergy
H2R
Intestinal Mucosa
Phosphorylation
Protein Kinase C
Mice
Inbred BALB C
biology
Chemistry
interleukin
Microbiota
3. Good health
Cell biology
microbe
Biochemistry
030220 oncology & carcinogenesis
gut
Signal transduction
Inflammation Mediators
signaling
Histamine
Signal Transduction
Diacylglycerol Kinase
Immunology
antihistamine
Article
03 medical and health sciences
Bacterial Proteins
lipid
Animals
Humans
Receptors
Histamine H2
Receptors
Histamine H1
intestine
Protein kinase C
Diacylglycerol kinase
Cyclin-dependent kinase 2
cytokines
IκBα
Lactobacillus
030104 developmental biology
inflammation
histamine receptors
Mutation
biology.protein
Zdroj: Mucosal immunology
Nature
ISSN: 1935-3456
1933-0219
Popis: Lactobacillus reuteri 6475 (Lr) of thehuman microbiome synthesizes histamine and can suppress inflammation via type 2 histamine receptor (H2R) activation in the mammalian intestine. Gut microbes such as Lr promote H2R signaling and may suppress H1R proinflammatory signaling pathways in parallel by unknown mechanisms. In this study,we identified a soluble bacterial enzyme known as diacylglycerol kinase (Dgk) from Lr that is secreted into the extracellular milieu and presumably into the intestinal lumen. DgK diminishes diacylglycerol (DAG) quantities in mammalian cells by promoting its metabolic conversion and causing reduced protein kinase C phosphorylation (pPKC) as a net effect in mammalian cells. We demonstrated that histamine synthesized by gut microbes (Lr) activates both mammalian H1R and H2R, but Lr-derived Dgk suppresses the H1R signaling pathway. Phospho-PKC and IKBα were diminished within the intestinal epithelium of mice and humans treated by wild-type (WT) Lr, but pPKC and IKBα were not decreased in treatment with δDdgkA Lr. Mucosal IL-6 and systemic interleukin (IL)-1α, eotaxin, and granulocyte colony-stimulating factor (G-CSF) were suppressed in WT Lr, but not in DdgkA Lr colonized mice. Collectively, the commensal microbe Lr may act as a "microbial antihistamine''by suppressing intestinal H1R-mediated proinflammatory responses via diminished pPKC-mediated mammalian cell signaling.
National Institutes of Health (U.S.) (grant R01 AT004326)
National Institutes of Health (U.S.) (grant UH3 DK083990)
National Institutes of Health (U.S.) (grant U01 CA170930)
National Institutes of Health (U.S.) (grant T32-OD010978-26)
National Institutes of Health (U.S.) (grant R01-OD011141)
National Institutes of Health (U.S.) (grant P30-ES002109)
National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (funded Texas Medical Center Digestive Diseases Center (DK56338))
BioGaia AB (Stockholm, Sweden)
Databáze: OpenAIRE
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