Ablation of the Cβ2 subunit of PKA in immune cells leads to increased susceptibility to systemic inflammation in mice

Moen, Line Victoria; Sener, Zeynep; Volchenkov, Roman; Svarstad, Anja Camilla; Eriksen, Aud Marit; Holen, Halvor L.; Skålhegg, Bjørn Steen

doi:10.1002/eji.201646809

Cited by 22 publications

(13 citation statements)

References 47 publications

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“…Nevertheless, TEAD1/p65 complex could regulate innate immune response (33). PRKACB-encoding Cβ2 regulates innate as well as adaptive immune sensitivity in vivo (34). TRIM68 could regulate IFN production by targeting TFG (35).…”

Section: Discussionmentioning

confidence: 99%

Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells

Zhang

Huang

et al. 2020

Ann Transl Med

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Background: To identify key microRNAs (miRNAs) and their target mRNAs related to gemcitabineresistant pancreatic cancer (PC) and investigate the association between gemcitabine-resistant-related miRNAs and mRNAs and immune infiltration.Methods: Expression profiles of miRNAs and mRNAs were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs and mRNAs (referred to as "DEmiRNAs" and "DEmRNAs", respectively) were distinguished between gemcitabine-resistant PC cells and its parental cells. The DEmRNAs targeted by the DEmiRNAs were retrieved using miRDB, microT, and Targetscan. Furthermore, GO and KEGG pathway enrichment analysis and GSEA were performed. The Kaplan-Meier plotter was used to analyze the prognosis of key DEmiRNAs and DEmRNAs on PC patients. The relationship between the key DEmRNAs and tumor-infiltrating immune cells in PC was investigated using CIBERSORT method using the LM22 signature as reference. Key infiltrating immune cells were further analyzed for the associations with prognosis of TCGA PAAD patients.Results: Four DEmiRNAs, including hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p, and hsa-miR-584-5p, were identified to target seven DEmRNAs, including MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6, individually, in gemcitabine-resistant PC cells versus parental cells. Gemcitabineresistant PC cells were enriched in proteasome-related, immune-related, and memory CD4 + T cell-related pathways, indicating a gemcitabine therapeutic effect on PC cells. All four DEmiRNAs and almost all DEmRNAs had an impact on the prognosis of PC patients. All seven DEmRNAs had remarkable effects on CD4 + memory T cells, which were affected by the gemcitabine therapeutic effect. Effector memory CD4 + T cells rather than central memory CD4 + T cells predicted a good prognosis according to the TCGA PAAD dataset.Conclusions: Gemcitabine resistance can alter the fraction of memory CD4 + T cells via hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p and hsa-miR-584-5p targeted MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6 network in PC.

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Section: Discussionmentioning

confidence: 99%

Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells

Zhang

Huang

et al. 2020

Ann Transl Med

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“…KEGG pathway analysis enriched several immune-related pathways, such as “MAPK signaling pathway,” “cAMP signaling pathway,” “endocytosis pathway,” “mTOR signaling pathway,” and “FoxO signaling pathway.” Generally, MAPK signaling pathway is thought to be involved in innate immune Toll-like receptor (TLR) expression47 and is important in the T-cell antigen receptor (TCR) signaling negative feedback loop 48. The cAMP signaling network is necessary for inducing the catalytic activity of protein kinase A (PKA) in splenocytes, lymphocytes, and thymocytes, which is important for regulating innate as well as adaptive immune sensitivities 49. cAMP was the first identified intracellular second messenger of extracellular ligand action.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA expression profile in chronic nonbacterial prostatitis revealed by next-generation small RNA sequencing

et al. 2019

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MicroRNAs (miRNAs) are considered to be involved in the pathogenic initiation and progression of chronic nonbacterial prostatitis (CNP); however, the comprehensive expression profile of dysregulated miRNAs, relevant signaling pathways, and core machineries in CNP have not been fully elucidated. In the current research, CNP rat models were established through the intraprostatic injection of carrageenan into the prostate. Then, next-generation sequencing was performed to explore the miRNA expression profile in CNP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) bioinformatical analyses were conducted to reveal the enriched biological processes, molecular functions, and cellular components and signaling pathways. As a result, 1224, 1039, and 1029 known miRNAs were annotated in prostate tissues from the blank control (BC), normal saline injection (NS), and carrageenan injection (CAR) groups ( n = 3 for each group), respectively. Among them, 84 miRNAs (CAR vs BC) and 70 miRNAs (CAR vs NS) with significantly different expression levels were identified. Compared with previously reported miRNAs with altered expression in various inflammatory diseases, the majority of deregulated miRNAs in CNP, such as miR-146b-5p, miR-155-5p, miR-150-5p, and miR-139-5p, showed similar expression patterns. Moreover, bioinformatics analyses have enriched mitogen-activated protein kinase (MAPK), cyclic adenosine monophosphate (cAMP), endocytosis, mammalian target of rapamycin (mTOR), and forkhead box O (FoxO) signaling pathways. These pathways were all involved in immune response, which indicates the critical regulatory role of the immune system in CNP initiation and progression. Our investigation has presented a global view of the differentially expressed miRNAs and potential regulatory networks containing their target genes, which may be helpful for identifying the novel mechanisms of miRNAs in immune regulation and effective target-specific theragnosis for CNP.

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“…However, as far as we know, no previous information about the role of any of these genes in ARMD reaction has been published. PRKACB is a serine/threonine protein kinase mediating cAMP signaling, with subsequent effects on a wide range of cellular processes, including proliferation, differentiation and inflammation [35,36]. Another, smaller network is centered on the pentose phosphate shunt -related gene phosphogluconate dehydrogenase (PGD), and includes genes related to carbohydrate, lipid and alcohol metabolism.…”

Section: Discussionmentioning

confidence: 99%

Gene expression in adverse reaction to metal debris around metal-on-metal arthroplasty: An RNA-Seq-based study

Pemmari

Leppänen

Paukkeri

et al. 2018

Journal of Trace Elements in Medicine and Biology

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Joint replacement surgery is a standard treatment of advanced osteoarthritis (OA). Since 2000, cobalt-chromium (CoCr) metal-on-metal (MoM) implants were widely used in hip arthroplasties. Some patients developed "adverse reaction to metal debris" (ARMD) around the prosthesis, resulting in a need for revision surgery. In the present study, we addressed the pathogenesis of ARMD by genome-wide expression analysis. Pseudosynovial ARMD tissue was obtained from revision surgery of Articular Surface Replacement (ASR, DePuy, Warsaw, IN, USA) hip arthroplasties. Control tissue was 1) OA synovium from primary hip arthroplasties and 2) inflammatory pseudosynovial tissue from metal-on-plastic (MoP) implant revisions. In ARMD tissue, the expression of 1446 genes was significantly increased and that of 1881 decreased as compared to OA synovium. Genes associated with immune response, tissue development and certain leukocyte signaling pathways were enriched in the differently (FC > 2) expressed genes. The network analysis proposed PRKACB, CD2, CD52 and CD53 as the central regulators of the greatest (FC > 10) differences. When ARMD tissue was compared to MoP tissue, the expression of 16 genes was significantly higher and that of 21 lower. Many of these genes were associated with redox homeostasis, metal ion binding and transport, macrophage activation and apoptosis. Interestingly, genes central to myofibroblast (AEBP1 and DES) and osteoclast (CCL21, TREM2 and CKB) development were upregulated in the MoP tissue. In network analysis, IL8, NQO1, GSTT1 and HMOX1 were identified as potential central regulators of the changes. In conclusion, excessive amounts of CoCr debris produced by MoM hip implants induces in a group of patients a unique adverse reaction characterized with enhanced expression of genes associated with inflammation, redox homeostasis, metal ion binding and transport, macrophage activation and apoptosis.

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Ablation of the Cβ2 subunit of PKA in immune cells leads to increased susceptibility to systemic inflammation in mice

Cited by 22 publications

References 47 publications

Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells

Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells

MicroRNA expression profile in chronic nonbacterial prostatitis revealed by next-generation small RNA sequencing

Gene expression in adverse reaction to metal debris around metal-on-metal arthroplasty: An RNA-Seq-based study

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