Dataset Information

Aging enhances release of exosomal cytokine mRNAs by A?1-42-stimulated macrophages.

ABSTRACT: Amyloid-?1-42 (A?) peptide effects on human models of central nervous system (CNS)-patrolling macrophages (Ms) and CD4 memory T-cells (CD4-Tms) were investigated to examine immune responses to A? in Alzheimer's disease. A? and lipopolysaccharide (LPS) elicited similar M cytokine and exosomal mRNA (ex-mRNA) responses. A?- and LPS-stimulated Ms from 20 ?65-yr-old subjects generated significantly more IL-1, TNF-?, and IL-6, but not IL-8 or IL-12, and significantly more ex-mRNAs for IL-6, TNF-?, and IL-12, but not for IL-8 or IL-1, than Ms from 20 matched 21- to 45-yr-old subjects. CD4-Tm generation of IL-2, IL-4, and IFN-? and, for young subjects, IL-10, but not IL-6, evoked by A? was significantly lower than with anti-T-cell antigen receptor antibodies (Abs). Abs significantly increased all CD4-Tm ex-mRNAs, but only IL-2 and IL-6 ex-mRNAs were increased by A?. There were no significant differences between cytokine and ex-mRNA responses of CD4-Tms from the old compared to the young subjects. M-derived serum exosomes from the old subjects had significantly higher IL-6 and IL-12 ex-mRNA levels than those from the young subjects, whereas there were no differences for CD4-Tm-derived serum exosomes. An A? level relevant to neurodegeneration elicited broad M cytokine and ex-mRNA responses that were significantly greater in the old subjects, but only narrow and age-independent CD4-Tm responses.

SUBMITTER: Mitsuhashi M

PROVIDER: S-EPMC3834783 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Aging enhances release of exosomal cytokine mRNAs by Aβ1-42-stimulated macrophages.

Mitsuhashi Masato M Taub Dennis D DD Kapogiannis Dimitrios D Eitan Erez E Zukley Linda L Mattson Mark P MP Ferrucci Luigi L Schwartz Janice B JB Goetzl Edward J EJ

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130906 12

Amyloid-β1-42 (Aβ) peptide effects on human models of central nervous system (CNS)-patrolling macrophages (Ms) and CD4 memory T-cells (CD4-Tms) were investigated to examine immune responses to Aβ in Alzheimer's disease. Aβ and lipopolysaccharide (LPS) elicited similar M cytokine and exosomal mRNA (ex-mRNA) responses. Aβ- and LPS-stimulated Ms from 20 ≥65-yr-old subjects generated significantly more IL-1, TNF-α, and IL-6, but not IL-8 or IL-12, and significantly more ex-mRNAs for IL-6, TNF-α, and ...[more]

PMID: 24014820

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Project description:BackgroundDysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-β, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release.MethodsELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1β relative potency were then employed to confirm the involvement of enriched pathways and TFs.ResultsLMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1β, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1β release.ConclusionIn this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.

Dataset Information

Aging enhances release of exosomal cytokine mRNAs by A?1-42-stimulated macrophages.

Publications

Aging enhances release of exosomal cytokine mRNAs by Aβ1-42-stimulated macrophages.

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