Dataset Information

NF-?B Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression.

ABSTRACT: The host response to pathogens through nuclear factor ?B (NF-?B) is an essential defense mechanism for eukaryotic organisms. NF-?B-mediated host responses inhibit bone and other connective tissue synthesis and are thought to affect the transcription of matrix proteins through multiple indirect pathways. We demonstrate that inhibiting NF-?B in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF-?B binding sites on osteocalcin (OC) or bone sialoprotein (Bsp) promoters rescues the negative impact of NF-?B on their transcription and that NF-?B can inhibit Wnt- and Bmp-induced OC and Bsp transcription, even when protein synthesis is inhibited, indicating a direct effect of NF-?B. This inhibition depends on p65-p50 NF-?B heterodimer formation and deacetylation by HDAC1 but is not affected by the noncanonical NF-?B pathway. Moreover, NF-?B reduces Runx2 and ?-catenin binding to OC/Bsp promoters independently of their nuclear localization. Thus, inflammatory signals stimulate the direct interaction of NF-?B with response elements to inhibit binding of ?-catenin and Runx2 binding to nearby consensus sites and reduce expression of matrix proteins. This direct mechanism provides a new explanation for the rapid decrease in new bone formation after inflammation-related NF-?B activation.

SUBMITTER: Tarapore RS

PROVIDER: S-EPMC4713353 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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NF-κB Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression.

Tarapore Rohinton S RS Lim Jason J Tian Chen C Pacios Sandra S Xiao Wenmei W Reid Daniel D Guan Hancheng H Mattos Marcelo M Yu Bo B Wang Cun-Yu CY Graves Dana T DT

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20150806 1

The host response to pathogens through nuclear factor κB (NF-κB) is an essential defense mechanism for eukaryotic organisms. NF-κB-mediated host responses inhibit bone and other connective tissue synthesis and are thought to affect the transcription of matrix proteins through multiple indirect pathways. We demonstrate that inhibiting NF-κB in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF-κB binding sites on osteocalcin (OC) or bone sialoprotei ...[more]

PMID: 26179215

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Project description:The nuclear factor kappa B (NF-κB) is a potent transcription factor, activation of which typically results in robust proinflammatory signaling and triggering of fast negative feedback modulators to avoid excessive inflammatory responses. Here, we report that infection of epithelial cells, including primary porcine respiratory epithelial cells, with the porcine alphaherpesvirus pseudorabies virus (PRV) results in the gradual and persistent activation of NF-κB, illustrated by proteasome-dependent degradation of the inhibitory NF-κB regulator IκB and nuclear translocation and phosphorylation of the NF-κB subunit p65. PRV-induced persistent activation of NF-κB does not result in expression of negative feedback loop genes, like the gene for IκBα or A20, and does not trigger expression of prototypical proinflammatory genes, like the gene for tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). In addition, PRV infection inhibits TNF-α-induced canonical NF-κB activation. Hence, PRV infection triggers persistent NF-κB activation in an unorthodox way and dramatically modulates the NF-κB signaling axis, preventing typical proinflammatory gene expression and the responsiveness of cells to canonical NF-κB signaling, which may aid the virus in modulating early proinflammatory responses in the infected host.IMPORTANCE The NF-κB transcription factor is activated via different key inflammatory pathways and typically results in the fast expression of several proinflammatory genes as well as negative feedback loop genes to prevent excessive inflammation. In the current report, we describe that infection of cells with the porcine alphaherpesvirus pseudorabies virus (PRV) triggers a gradual and persistent aberrant activation of NF-κB, which does not result in expression of hallmark proinflammatory or negative feedback loop genes. In addition, although PRV-induced NF-κB activation shares some mechanistic features with canonical NF-κB activation, it also shows remarkable differences; e.g., it is largely independent of the canonical IκB kinase (IKK) and even renders infected cells resistant to canonical NF-κB activation by the inflammatory cytokine TNF-α. Aberrant PRV-induced NF-κB activation may therefore paradoxically serve as a viral immune evasion strategy and may represent an important tool to unravel currently unknown mechanisms and consequences of NF-κB activation.

Dataset Information

NF-?B Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression.

Publications

NF-κB Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression.

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