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Human monocytes have increased IFN-?-mediated IL-15 production with age alongside altered IFN-? receptor signaling.

ABSTRACT: IL-15 is involved in regulating host defense and inflammation. Monocytes produce the biologically active cell surface IL-15 in response to IFN-?. Although aging can alter the immune system, little is known about whether and how aging affects IFN-?-mediated IL-15 production in human monocytes. We showed that monocytes of healthy older adults (age ? 65) had increased cell surface IL-15 expression in response to IFN-? compared to those of healthy young adults (age ? 40). This finding stems in part from increased IFN-? receptor (R)1/2 expression on monocytes in older adults, leading to enhanced STAT1 activation and interferon regulatory factor 1 synthesis with increased IL15 gene expression. Our study suggests that with aging the IFN-?-mediated IL-15 production pathway in human monocytes is uncompromised, but rather augmented, and could be considered as a therapeutic target point to modulate host defense and inflammation in older adults.

SUBMITTER: Lee N

PROVIDER: S-EPMC4018768 | biostudies-literature | 2014 May-Jun

REPOSITORIES: biostudies-literature

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Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling.

Lee Naeun N Shin Min Sun MS Kang Ki Soo KS Yoo Seung-Ah SA Mohanty Subhasis S Montgomery Ruth R RR Shaw Albert C AC Kang Insoo I

Clinical immunology (Orlando, Fla.) 20140319 1-2

IL-15 is involved in regulating host defense and inflammation. Monocytes produce the biologically active cell surface IL-15 in response to IFN-γ. Although aging can alter the immune system, little is known about whether and how aging affects IFN-γ-mediated IL-15 production in human monocytes. We showed that monocytes of healthy older adults (age ≥ 65) had increased cell surface IL-15 expression in response to IFN-γ compared to those of healthy young adults (age ≤ 40). This finding stems in part ...[more]

PMID: 24657713

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Project description:IntroductionToll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1? in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis.MethodsTo induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration.ResultsCompared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-?, IL-12p35 and IL-1? transcript levels in the joints, but high transforming growth factor (TGF)-? expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-? and IL-1? production via T-bet and pro-IL-1? production. Recombinant IL-12, IFN-? and IL-1? administration restored arthritis, but reduced joint TGF-? levels in TLR4-/- mice. Moreover, a TGF-? blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4-/- mice.ConclusionTLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-? and IL-1? production, which suppresses TGF-? production, thereby promoting antibody-induced arthritis.

Dataset Information

Human monocytes have increased IFN-?-mediated IL-15 production with age alongside altered IFN-? receptor signaling.

Publications

Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling.

Similar Datasets

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