Dataset Information

CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-? Production in a Macrophage Subset.

ABSTRACT: In response to GM-CSF or M-CSF, macrophages (M?) can acquire pro- or anti-inflammatory properties, respectively. Given the importance of CD14 and Toll-like receptor (TLR) 4 in lipopolysaccharide (LPS)-induced signaling, we studied the effect of anti-CD14 antibody mediated CD14 blockade on LPS-induced cytokine production, signal transduction and on the expression levels of CD14 and TLR4 in GM-M? and M-M?. We found M-M? to express higher levels of both surface antigens and to produce more interferon (IFN)-? and interleukin-10, but less tumor necrosis factor (TNF)-? than GM-M?. Blockage of CD14 at high LPS concentrations increased the production of proinflammatory cytokines and decreased that of IFN-? in M-M? but not in GM-M?. We show that phosphorylation states of signaling molecules of the MyD88 (myeloid differentiation primary response 88), TRIF (TIR-domain-containing adapter-inducing IFN-?) and MAPK (mitogen-activated protein kinase) pathways are not altered in any way that would account for the cytokine overshoot reaction. However, CD14 blockage in M-M? decreased TLR4 and CD14 expression levels, regardless of the presence of LPS, indicating that the loss of the surface molecules prevented LPS from initiating TRIF signaling. As TNF-? synthesis was even upregulated under these experimental conditions, we suggest that TRIF is normally involved in restricting LPS-induced TNF-? overproduction. Thus, surface CD14 plays a decisive role in the biological response by determining LPS-induced signaling.

SUBMITTER: Grahnert A

PROVIDER: S-EPMC6738177 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-α Production in a Macrophage Subset.

Grahnert Anja A Weiss Ronald R Schilling Erik E Stanslowsky Nancy N Sack Ulrich U Hauschildt Sunna S

Journal of innate immunity 20190117 4

In response to GM-CSF or M-CSF, macrophages (MΦ) can acquire pro- or anti-inflammatory properties, respectively. Given the importance of CD14 and Toll-like receptor (TLR) 4 in lipopolysaccharide (LPS)-induced signaling, we studied the effect of anti-CD14 antibody mediated CD14 blockade on LPS-induced cytokine production, signal transduction and on the expression levels of CD14 and TLR4 in GM-MΦ and M-MΦ. We found M-MΦ to express higher levels of both surface antigens and to produce more interfer ...[more]

PMID: 30654377

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Project description:Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-kappaB) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFalpha) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFalpha synthesis in a manner that involved transcriptional repression of the TNFalpha promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFalpha promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFalpha cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFalpha production. Moreover, because Tat activates both RelB and TNFalpha in microglia, and because Tat induces inflammatory TNFalpha synthesis via NF-kappaB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-kappaB activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND.

Dataset Information

CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-? Production in a Macrophage Subset.

Publications

CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-α Production in a Macrophage Subset.

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