Modelling the dynamics of signalling pathways

2008 ◽  
Vol 45 ◽  
pp. 1-28 ◽  
Author(s):  
Sree N. Sreenath ◽  
Kwang-Hyun Cho ◽  
Peter Wellstead
Keyword(s):  
Chemical Kinetics ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Stochastic Chemical Kinetics ◽  
Discrete State ◽  
Explicit Mention ◽  
Decision Making Processes ◽  
The Right

In the present chapter we discuss methodologies for the modelling, calibration and validation of cellular signalling pathway dynamics. The discussion begins with the typical range of techniques for modelling that might be employed to go from the chemical kinetics to a mathematical model of biochemical pathways. In particular, we consider the decision-making processes involved in selecting the right mechanism and level of detail of representation of the biochemical interactions. These include the choice between (i) deterministic and stochastic chemical kinetics representations, (ii) discrete and continuous time models and (iii) representing continuous and discrete state processes. We then discuss the task of calibrating the models using information available in web-based databases. For situations in which the data are not available from existing sources we discuss model calibration based upon measured data and system identification methods. Such methods, together with mathematical modelling databases and computational tools, are often available in standard packages. We therefore make explicit mention of a range of popular and useful sites. As an example of the whole modelling and calibration process, we discuss a study of the cross-talk between the IL-1 (interleukin-1)-stimulated NF-κB (nuclear factor κB) pathway and the TGF-β (transforming growth factor β)-stimulated Smad2 pathway.

Priming IKKβ kinase for action

2014 ◽  
Vol 463 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Steven C. Ley ◽  
Rudi Beyaert
Keyword(s):  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Kinase Domain ◽  
Activation Loop ◽  
Iκb Kinase ◽  
Biochemical Journal ◽  
Upstream Kinase

IKKβ (IκB kinase β) is a core component of signalling pathways that control the activation of NF-κB (nuclear factor κB) transcription factors, which regulate many physiological processes, including cell survival, immunity and DNA-damage responses. Like many kinases, activation of IKKβ requires phosphorylation of the activation loop of its kinase domain. Different upstream protein kinases, and IKKβ itself, have been reported to directly phosphorylate and activate IKKβ in vitro, but the exact molecular mechanism of IKKβ activation in cells has remained unclear. In a recent article in the Biochemical Journal, Zhang and co-workers showed that IKKβ is activated by two sequential phosphorylations of its activation loop in response to TNF (tumour necrosis factor), IL-1 (interleukin-1) and TLR (Toll-like receptor) ligands. Using a combination of biochemical and genetic approaches, they demonstrate that IKKβ is first phosphorylated by the upstream kinase TAK1 [TGFβ (transforming growth factor β)-activated kinase-1] at Ser177, which then serves as a priming signal for subsequent IKKβ autophosphorylation at Ser181. This study resolves two apparently conflicting earlier models of IKKβ activation into a single unified model, and suggests that the IKKβ activation loop may integrate distinct ‘upsteam’ signals to activate NF-κB.

scholarly journals TAK1 Is Essential for Osteoclast Differentiation and Is an Important Modulator of Cell Death by Apoptosis and Necroptosis

2012 ◽  
Vol 33 (3) ◽  
pp. 582-595 ◽  
Author(s):  
Betty Lamothe ◽  
YunJu Lai ◽  
Min Xie ◽  
Michael D. Schneider ◽  
Bryant G. Darnay
Keyword(s):  
Cell Death ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Osteoclast Differentiation ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Interacting Protein ◽  
Iκb Kinase ◽  
Mitogen Activated Protein ◽  
Macrophage Colony

ABSTRACTTransforming growth factor β (TGF-β)-activated kinase 1 (TAK1), a mitogen-activated protein 3 (MAP3) kinase, plays an essential role in inflammation by activating the IκB kinase (IKK)/nuclear factor κB (NF-κB) and stress kinase (p38 and c-Jun N-terminal kinase [JNK]) pathways in response to many stimuli. The tumor necrosis factor (TNF) superfamily member receptor activator of NF-κB ligand (RANKL) regulates osteoclastogenesis through its receptor, RANK, and the signaling adaptor TRAF6. Because TAK1 activation is mediated through TRAF6 in the interleukin 1 receptor (IL-1R) and toll-like receptor (TLR) pathways, we sought to investigate the consequence of TAK1 deletion in RANKL-mediated osteoclastogenesis. We generated macrophage colony-stimulating factor (M-CSF)-derived monocytes from the bone marrow of mice with TAK1 deletion in the myeloid lineage. Unexpectedly, TAK1-deficient monocytes in culture died rapidly but could be rescued by retroviral expression of TAK1, inhibition of receptor-interacting protein 1 (RIP1) kinase activity with necrostatin-1, or simultaneous genetic deletion of TNF receptor 1 (TNFR1). Further investigation using TAK1-deficient mouse embryonic fibroblasts revealed that TNF-α-induced cell death was abrogated by the simultaneous inhibition of caspases and knockdown of RIP3, suggesting that TAK1 is an important modulator of both apoptosis and necroptosis. Moreover, TAK1-deficient monocytes rescued from programmed cell death did not form mature osteoclasts in response to RANKL, indicating that TAK1 is indispensable to RANKL-induced osteoclastogenesis. To our knowledge, we are the first to report that mice in which TAK1 has been conditionally deleted in osteoclasts develop osteopetrosis.

A mechanism for the suppression of interleukin-1-induced nuclear factor κB activation by protein phosphatase 2Cη-2

2009 ◽  
Vol 423 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Takeaki Henmi ◽  
Kazutaka Amano ◽  
Yuko Nagaura ◽  
Kunihiro Matsumoto ◽  
Seishi Echigo ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Ectopic Expression ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Signalling Pathway ◽  
Nuclear Factor ◽  
Interfering Rna ◽  
Signalling Cascade

IL-1 (interleukin-1) is a pro-inflammatory cytokine that has a variety of effects during the process of inflammation. Stimulating cells with IL-1 initiates a signalling cascade that includes the activation of NF-κB (nuclear factor κB), and subsequently induces a variety of inflammatory genes. Although the molecular mechanism for the IL-1-induced activation of NF-κB has been well documented, much less is known about the mechanism by which protein phosphatases down-regulate this pathway. Here we show that mouse PP2Cη-2 (protein serine/threonine phosphatase 2Cη-2), a novel member of the protein serine/threonine phosphatase 2C family, inhibits the IL-1–NF-κB signalling pathway. Ectopic expression of PP2Cη-2 in human embryonic kidney HEK293IL-1RI cells inhibited the IL-1-induced activation of NF-κB. TAK1 (transforming-growth-factor-β-activated kinase 1) mediates the IL-1 signalling pathway to NF-κB, and we observed that the TAK1-induced activation of NF-κB was suppressed by PP2Cη-2 expression. Expression of IKKβ [IκB (inhibitory κB) kinase β], which lies downstream of TAK1, activates NF-κB, and this activation was also readily reversed by PP2Cη-2 co-expression. Additionally, PP2Cη-2 knockdown with small interfering RNA further stimulated the IL-1-enhanced phosphorylation of IKKβ and destabilization of IκBα in HeLa cells. PP2Cη-2 knockdown also increased the IL-1-induced expression of IL-6 mRNA. Furthermore, IKKβ was readily dephosphorylated by PP2Cη-2 in vitro. These results suggest that PP2Cη-2 inhibits the IL-1–NF-κB signalling pathway by selectively dephosphorylating IKKβ.

Dual Therapy Deflazacort/Doxycyclyne Is Better Than Deflazacort Monotherapy to Alleviate Cardiomyopathy in Dystrophin-Deficient mdx Mice

2016 ◽  
Vol 22 (5) ◽  
pp. 458-466 ◽  
Author(s):  
Juliano Alves Pereira ◽  
Adriana Fogagnolo Mauricio ◽  
Maria Julia Marques ◽  
Humberto Santo Neto
Keyword(s):  
Transforming Growth Factor ◽  
Combined Therapy ◽  
Dual Therapy ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Markers Of Inflammation ◽  
The Right ◽  
Better Than

Cardiomyopathy related to the absence of dystrophin is an important feature in Duchenne muscular dystrophy (DMD) and in the mdx mouse. Doxycycline (DOX) could be a potential therapy for mdx skeletal muscles dystrophy. We investigated whether the corticoid deflazacort (DFZ) plus DOX could improve cardiac mdx dystrophy better than DFZ alone, later (17 months) in dystrophy. Mdx mice (8 months old) received DFZ/DOX or DFZ for 9 months. The combined therapy was greater than DFZ in reducing fibrosis (60% decrease with DFZ/DOX and 40% with DFZ alone) in the right ventricle and transforming growth factor β levels (6.8 ± 3.2 in untreated mdx mice, 2.8 ± 1.4 in combined therapy, and 4.6 ± 1.7 in DFZ; P < .05). Combined therapy more effectively ameliorated cardiac dysfunction (electrocardiogram [ECG]) than DFZ. Improvements were seen in the cardiomyopathy index (0.8 ± 0.1 in combined therapy and 1.0 ± 0.2 in DFZ), heart rate (418 ± 46 bpm in combined therapy and 457 ± 29 bpm in DFZ), QRS interval (11.3 ± 2 in combined therapy and 13.6 ± 1 in DFZ), and Q wave amplitude (−40.7 ± 21 in combined therapy and −90.9 ± 36 in DFZ). Both therapies decreased markers of inflammation (tumor necrosis factor α, nuclear factor κB, and metalloproteinase 9). DFZ/DOX improved mdx cardiomyopathy at this stage of the disease, supporting further clinical investigations.

Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

2007 ◽  
Vol 67 (4) ◽  
pp. 559-562 ◽  
Author(s):  
K Warstat ◽  
T Pap ◽  
G Klein ◽  
S Gay ◽  
W K Aicher
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Synovial Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
The Matrix ◽  
Specific Tissue ◽  
Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

scholarly journals TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy

2020 ◽  
Vol 69 (12) ◽  
pp. 1215-1234
Author(s):  
Hanxu Zeng ◽  
Xiangming Qi ◽  
Xingxin Xu ◽  
Yonggui Wu
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Lentiviral Vector ◽  
Hypoxia Inducible Factor ◽  
Damage Index ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Inflammatory Factors

Abstract Objective and design Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN. Methods TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. Results We found that TAB1/NF-κB/HIF-1α, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown. Conclusions Our results suggest that the TAB1/NF-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN.

scholarly journals Inflammatory cytokines in the pathogenesis of cardiovascular disease and cancer

2020 ◽  
Vol 8 ◽  
pp. 205031212096575 ◽  
Author(s):  
Mohammad Nurul Amin ◽  
Shafayet Ahmed Siddiqui ◽  
Md Ibrahim ◽  
Md Lukman Hakim ◽  
Md. Salim Ahammed ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β ◽  
Causative Factor ◽  
Interleukin 10 ◽  
Cardiac Events ◽  
Human Immune System ◽  
Cancer Pathogenesis

Inflammatory cytokines are highly inducible small glycoproteins or regulatory proteins of low molecular weight secreted by different cell types. They regulate intercellular communication and mediate a number of physiological functions in the human immune system. Numerous prospective studies report that inflammatory cytokines strongly predict coronary artery disease, myocardial infarction, heart failure and other adverse cardiac events. Inflammatory cascade is believed to be a causative factor in the development of atherosclerotic process. Several aspects of atherogenesis are accelerated by cytokines. This article provides an overall overview of current understanding of cytokines in various cardiovascular events. Besides, inflammatory cytokines trigger cellular events that can induce malignancy and carcinogenesis. Elevated expression of several cytokines such as interleukin-1, interleukin-6, interleukin-10, tumor necrosis factor-α, macrophage migration inhibitory factor and transforming growth factor-β are involved in tumor initiation and progression. Thus, they exert a pivotal role in cancer pathogenesis. This review highlights the role of several cytokines in various events of tumorigenesis. Actually, this article summarizes the contributions of cytokines in the pathogenesis of cardiovascular disease and cancer.

The Concentration of Plasma Provides Additional Bioactive Proteins in Platelet and Autologous Protein Solutions

2019 ◽  
Vol 47 (8) ◽  
pp. 1955-1963 ◽  
Author(s):  
Sean M. Muir ◽  
Natalie Reisbig ◽  
Michael Baria ◽  
Christopher Kaeding ◽  
Alicia L. Bertone
Keyword(s):  
Growth Factor ◽  
Receptor Antagonist ◽  
Laboratory Study ◽  
Whole Blood ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Waste Product ◽  
Transforming Growth Factor Β ◽  
Interleukin 1 Receptor Antagonist ◽  
Unique Source

Background: Currently, platelet-poor plasma (PPP) is a discarded waste product of platelet-rich plasma (PRP) and may contain valuable proteins. Purpose/Hypothesis: The study’s goal was to evaluate the concentration of plasma as a potential additive biotherapy for the treatment of osteoarthritis. We hypothesized that a novel polyacrylamide concentration device would efficiently concentrate insulin-like growth factor–1 (IGF-1) from PPP and be additive to PRP or autologous protein solution (APS). Study Design: Descriptive laboratory study. Methods: A laboratory study was conducted with human and equine whole blood from healthy volunteers/donors. Fresh samples of blood and plasma were processed and characterized for platelet, white blood cell, and growth factor/cytokine content and then quantified by enzyme-linked immunosorbent assays specific for IGF-1, transforming growth factor–β, interleukin-1β, and interleukin-1 receptor antagonist as representatives of cartilage anabolic and inflammatory mediators. Results: A potent cartilage anabolic protein, IGF-1, was significantly concentrated by the polyacrylamide concentration device in both human and equine PPP. The polyacrylamide device also substantially increased plasma proteins over whole blood, most dramatically key proteins relevant to the treatment of osteoarthritis, including transforming growth factor–β (29-fold over blood) and interleukin-1 receptor antagonist (70-fold over plasma). Conclusion: Concentrated PPP is a unique source for biologically relevant concentrations of IGF-1. PRP and APS can produce greater concentrations of other anabolic and anti-inflammatory proteins not found in plasma. Clinical Relevance: The polyacrylamide device efficiently concentrated PPP to create a unique source of IGF-1 that may supplement orthopaedic biologic therapies.

Sign in / Sign up

Export Citation Format

Share Document