scholarly journals Temperature regulates NF-κB dynamics and function through timing of A20 transcription

2018 ◽  
Vol 115 (22) ◽  
pp. E5243-E5249 ◽  
Author(s):  
C. V. Harper ◽  
D. J. Woodcock ◽  
C. Lam ◽  
M. Garcia-Albornoz ◽  
A. Adamson ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Early Response ◽  
Strong Temperature Dependence ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Multidimensional Information ◽  
Dynamics And Function ◽  
And Function ◽  
Necrosis Factor

NF-κB signaling plays a pivotal role in control of the inflammatory response. We investigated how the dynamics and function of NF-κB were affected by temperature within the mammalian physiological range (34 °C to 40 °C). An increase in temperature led to an increase in NF-κB nuclear/cytoplasmic oscillation frequency following Tumor Necrosis Factor alpha (TNFα) stimulation. Mathematical modeling suggested that this temperature sensitivity might be due to an A20-dependent mechanism, and A20 silencing removed the sensitivity to increased temperature. The timing of the early response of a key set of NF-κB target genes showed strong temperature dependence. The cytokine-induced expression of many (but not all) later genes was insensitive to temperature change (suggesting that they might be functionally temperature-compensated). Moreover, a set of temperature- and TNFα-regulated genes were implicated in NF-κB cross-talk with key cell-fate–controlling pathways. In conclusion, NF-κB dynamics and target gene expression are modulated by temperature and can accurately transmit multidimensional information to control inflammation.

Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha–mediated effect

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1610-1619 ◽  
Author(s):  
Helen A. Papadaki ◽  
Heraklis D. Kritikos ◽  
Claudia Gemetzi ◽  
Helen Koutala ◽  
Judith C. W. Marsh ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Tumor Necrosis ◽  
Stromal Cell ◽  
Cell Function ◽  
Necrosis Factor Alpha ◽  
Cd34 Cells ◽  
Factor Alpha ◽  
And Function ◽  
Necrosis Factor

Based on previous reports for impaired hematopoiesis in rheumatoid arhrtitis (RA), and in view of the current interest in exploring the role of autologous stem cell transplantation (ASCT) as an alternative treatment in patients with resistant disease, we have evaluated bone marrow (BM) progenitor cell reserve and function and stromal cell function in 26 patients with active RA. BM progenitor cells were assessed using flow cytometry and clonogenic assays in short-term and long-term BM cultures (LTBMCs). BM stroma function was assessed by evaluating the capacity of preformed irradiated LTBMC stromal layers to support the growth of normal CD34+ cells. We found that RA patients exhibited low number and increased apoptosis of CD34+ cells, defective clonogenic potential of BM mononuclear and purified CD34+ cells, and low progenitor cell recovery in LTBMCs, compared with healthy controls (n = 37). Patient LTBMC stromal layers failed to support normal hematopoiesis and produced abnormally high amounts of tumor necrosis factor alpha (TNFα). TNFα levels in LTBMC supernatants inversely correlated with the proportion of CD34+ cells and the number of colony-forming cells, and positively with the percentage of apoptotic CD34+ cells. Significant restoration of the disturbed hematopoiesis was obtained following anti-TNFα treatment in 12 patients studied. We concluded that BM progenitor cell reserve and function and BM stromal cell function are defective in RA probably due, at least in part, to a TNFα-mediated effect. The role of these abnormalities on stem cell harvesting and engraftment in RA patients undergoing ASCT remains to be clarified.

scholarly journals Identification of Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor in Rheumatoid Arthritis Using Network Pharmacology and Molecular Docking

2021 ◽  
Vol 12 ◽  
Author(s):  
Liang Liang Bai ◽  
Hao Chen ◽  
Peng Zhou ◽  
Jun Yu
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Target Genes ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Receptor Signaling Pathway ◽  
Factor Alpha ◽  
Necrosis Factor

Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (white peony, WP) in treating immune inflammatory diseases of rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis) by using network pharmacology and molecular docking.Methods: In this study, the ingredient of WP and the potential inflammatory targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard, and OMIM databases, respectively. The establishment of the RA–WP-potential inflammatory target gene interaction network was accomplished using the STRING database. Network maps of the WP–RA-potential inflammatory target gene network were constructed using Cytoscape software. Gene ontology (GO) and the biological pathway (KEGG) enrichment analyses were used to further explore the RA mechanism and therapeutic effects of WP. Molecular docking technology was used to analyze the optimal effective components from WP for docking with TNF-α.Results: Thirteen active ingredients and 71 target genes were screened from WP, and 49 of the target genes intersected with RA target inflammatory genes and were considered potential therapeutic targets. Network pharmacological analysis showed that the WP active ingredients such as mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA inflammatory target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, and CHRM2, respectively. The immune-inflammatory signaling pathways of the active ingredients for the treatment of RA are the TNF-α signaling pathway, Toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated protein kinase, etc. Molecular docking results suggested that mairin was the most appropriate natural TNFis.Conclusion: Our findings provide an essential role and basis for further immune-inflammatory studies into the molecular mechanisms of WP and TNFis development in RA.

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