Alternative splicing regulation in tumor necrosis factor‑mediated inflammation (Review)

López–Urrutia, Eduardo; Campos‐Parra, Alma D.; Pérez‐Plasencia, Carlos

doi:10.3892/ol.2017.6905

Cited by 6 publications

(10 citation statements)

References 49 publications

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“…Estrogen receptor beta (ESR2), which is targeted by Zhi Qiao, is expressed in the gastrointestinal tract and provides a therapeutic strategy to treat patients suffering from gastrointestinal diseases induced by excessive neuronal/glial cell damage (D’Errico et al, 2018). Compounds in Mu Gua target tumor necrosis factor (TNF), which is a well-known cytokine involved in inflammatory processes (López-Urrutia et al., 2017). The progesterone receptor (PGR) is targeted by Ling Zhi and plays a role in reducing the risk of osteoporosis (Zhong et al., 2017).…”

Section: Resultsmentioning

confidence: 99%

“…A total of 16 targets participate in the IL-17 signaling pathway, which is a novel therapeutic target for the treatment of nonalcoholic fatty liver disease via the modulation of hepatocellular damage (Harley et al., 2014). The TNF signaling pathway (involving 14 targets) is one of the most studied pathways involved in the regulation of the inflammatory response (López-Urrutia et al., 2017).…”

Section: Resultsmentioning

confidence: 99%

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Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

et al. 2019

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Obesity is a multi-factorial chronic disease that has become a serious, prevalent, and refractory public health challenge globally because of high rates of various complications. Traditional Chinese medicines (TCMs) as a functional food are considered to be a valuable and readily available resource for treating obesity because of their better therapeutic effects and reduced side effects. However, their “multi-compound” and “multi-target” features make it extremely difficult to interpret the potential mechanism underlying the anti-obesity effects of TCMs from a holistic perspective. An innovative systems-pharmacology approach was employed, which combined absorption, distribution, metabolism, and excretion screening and multiple target fishing, gene ontology enrichment analysis, network pharmacology, and pathway analysis to explore the potential therapeutic mechanism of weight-loss herbal intervention therapy in obesity and related diseases. The current study provides a promising approach to facilitate the development and discovery of new botanical drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

et al. 2019

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“…Aberrant alternative splicing can substantially affect cellular function and is associated with disease. For example, alternative splicing of TNFα-regulated genes (such as Tnfaip3/A20) produces protein variants with distinct roles in cell death and cell survival [55].…”

Section: Discussionmentioning

confidence: 99%

PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

Léveillé

Besse-Patin

Jouvet

et al. 2019

Preprint

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Common Abbreviations:Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α); nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); tumor necrosis factor alpha (TNFα); non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH) Transcript Profiling: GEO accession number GSE132458ABSTRACT Background and Aims: Liver is exposed to changing metabolic and inflammatory environments.It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1α is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation in several tissues. However, it is not known how PGC-1α integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants expressed from different promoters. Methods: Tissue samples from transgenic mice and humans with fatty liver disease were analyzed for expression of PGC-1α isoforms and apoptosis caused by inflammatory damage.Primary mouse hepatocytes were used to identify effectors of PGC-1α activity downstream of TNFα. Results: We show in human liver that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) preferentially activated the alternative PPARGC1A promoter. Gene expression analysis in primary mouse hepatocytes identified shared and isoform-specific roles for PGC-1α variants in response to TNFα. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα signaling revealed that PGC-1α4 influenced several pathways related to innate immunity and cell death. Gain-and loss-of-function models showed that PGC-1α4 specifically enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNFα or LPS. This was in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network, but did not prevent liver cell death. Conclusions:We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation and identify PGC-1α4 as an important mitigator of apoptosis.

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“…Previous high-throughput sequencing studies have annotated alternatively spliced isoforms of virtually all of these transcripts and in some cases, isoforms have been functionally characterized. For example, alternative splicing of TRAFs, which mediate TNF signaling and MAPK activation, is thought to play an important role in inflammation and cancer development [53] and alternative splicing of TRIM family genes has been shown to generate dominant negative isoforms that regulate nucleic acid sensing pathways [54,55].…”

Section: Sr/hnrnps-mediated Alternative Splicing Events Are Not Commomentioning

confidence: 99%

Global transcriptomics reveals specialized roles for splicing regulatory proteins in the macrophage innate immune response

West

Wagner

Scott

et al. 2020

Preprint

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Pathogen sensing via pattern recognition receptors triggers massive reprogramming of macro-phage gene expression. While the signaling cascades and transcription factors that activate these responses are well-known, the role of post-transcriptional RNA processing in modulating innate immune gene expression remains understudied. Recent phosphoproteomics analyses revealed that members of the SR and hnRNP families of splicing regulatory proteins are dynamically post-translationally modified in infected macrophages. To begin to test if these splicing factors play a privileged role in controlling the innate immune transcriptome, we analyzed steady state gene expression and alternatively spliced isoform production in ten SR/hnRNP knockdown RAW 264.7 macrophage cell lines following infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (Salmonella). We identified thousands of transcripts whose abundance was increased or decreased by SR/hnRNP knockdown in macrophages. We observed that different SR/hnRNPs control the expression of distinct gene regulons in uninfected and Salmonella-infected macrophages, with several key innate immune genes (Nos2, Mx1, Il1a) relying on multiple SR/hnRNPs to maintain proper induction and/or repression. Knockdown of SR/hnRNPs promoted differential isoform usage (DIU) for a number of key immune sensors and signaling molecules and many of these splicing changes were again, distinct in uninfected and Salmonella-infected macrophages. Finally, after observing a surprising degree of similarity between the DEGs and DIUs in hnRNP K and U knockdown macrophages, we found that these cells are better able to restrict vesicular stomatitis virus replication than control cells, supporting a role for these hnRNPs in controlling infection outcomes in macrophages ex vivo. Based on these findings, we conclude that many innate immune genes have evolved to rely on one or more splicing regulatory factors to ensure the proper timing and magnitude of their induction, bolstering a model wherein pre-mRNA splicing is a critical regulatory node in the innate immune response.

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Alternative splicing regulation in tumor necrosis factor‑mediated inflammation (Review)

Cited by 6 publications

References 49 publications

Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

Global transcriptomics reveals specialized roles for splicing regulatory proteins in the macrophage innate immune response

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