Suppression of IL-12 Production by Tristetraprolin through Blocking NF-кB Nuclear Translocation

Gu, Ling; Ning, Huan; Xu, Qian; Qi, Huang; Hou, Rong; Almourani, Rajaa; Fu, Mingui; Blackshear, Perry J.; Liu, Jianguo

doi:10.4049/jimmunol.1300126

Cited by 28 publications

(25 citation statements)

References 47 publications

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“…Knockdown of this inhibition results in enhanced production of inflammatory cytokines(19). Cytokine response to NF-κB signaling is dependent on the profile of subunit activation(52), and is subject to coordinated regulation by other signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Hussman¹,

Beecham

Schmidt

et al. 2016

Genes Immun

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Objective To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS). Methods The Genome-Wide Association Studies noise-reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on significance of linkage disequilibrium (LD) blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Results The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte, and leukocyte activation (p=6.1E-15, 1.2E-14, and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. Conclusions A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.

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Section: Discussionmentioning

confidence: 99%

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Hussman¹,

Beecham

Schmidt

et al. 2016

Genes Immun

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“…One possible explanation for this discrepancy is that some other CCCH zinc finger proteins may compensate for the effect of MCPIP1 deficiency on NF-κB activation. TTP was also reported to negatively regulate NF-κB signalling by acting as a co-repressor or by interfering with the nuclear translocation of p65 (REFS 47–49) (FIG. 3).…”

Section: Regulation Of Immune Cell Activationmentioning

confidence: 99%

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

2016

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Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis.

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“…Plasmin cleavage of iC3b regulates macrophage IL-12 secretion IL-12 is produced by activated immune cells, initiates Tcell responses and induces opsonic and complement-fixing antibodies [19]. Regulation of IL-12 expression is complex, but its release is suppressed by iC3b via CR signaling pathways.…”

Section: Plasmin Dampens Ic3b-mediated Phagocytosis By Macrophagesmentioning

confidence: 99%

Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses

Foley

Peterson

Lei

et al. 2015

Journal of Thrombosis and Haemostasis

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Summary. Background: The plasmin(ogen) and complement systems are simultaneously activated at sites of tissue injury, participating in hemostasis, wound healing, inflammation and immune surveillance. In particular, the C3 proteolytic fragment, iC3b, and its degradation product C3dg, which is generated by cleavage by factor I (FI) and the cofactor complement receptor CR1, are important in bridging innate and adaptive immunity. Via a thioester (TE) bond, iC3b and C3dg covalently tag pathogens, modulating phagocytosis and adaptive immune responses. Objective: To examine plasmin-mediated proteolysis of iC3b, and to evaluate the functional consequences, comparing the effects with products generated by FI/CR1 cleavage of iC3b. Methods: Dose-dependent and time-dependent plasmin-mediated cleavage of iC3b were characterized by analytical gel electrophoresis. The properties of the resultant TE bond-containing fragments on phagocytosis and induction of pro-inflammatory cytokines were measured in cell culture systems. Results: At low concentrations, plasmin effectively cleaves iC3b, but at numerous previously undescribed sites, giving rise to novel C3c-like and C3dg-like moieties, the latter of which retain the TE bond. When attached to zymosan or erythrocytes and exposed to THP-1 macrophages, the C3dg-like proteins behave almost identically to the bona fide C3dg, yielding less phagocytosis as compared with the opsonin iC3b, and more macrophage secretion of the pro-inflammatory cytokine, IL-12. Conclusion: Plasmin cleavage of iC3b provides a complement regulatory pathway that is as efficient as FI/CR1 but does not require a cellular cofactor.

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Suppression of IL-12 Production by Tristetraprolin through Blocking NF-кB Nuclear Translocation

Cited by 28 publications

References 47 publications

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses

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