Signalling networks, inflammation and innate immunity

2003 ◽  
Vol 31 (6) ◽  
pp. 1462-1471 ◽  
Author(s):  
S.K. Dower ◽  
E.E. Qwarnstrom
Keyword(s):  
Real Time ◽  
Fluorescent Protein ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Biological Significance ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Screening Methods ◽  
Expression Screening ◽  
Tir Domain

We have been analysing the signalling systems that couple to receptors of the TIR (Toll/interleukin-1 receptor) family, which signal through a common cytoplasm region; the TIR domain. These systems are of both practical and fundamental biological significance, being central to the pathogenesis of chronic inflammatory diseases such as atherosclerosis, to host defence throughout the biological world, and are ancient in the context of life on earth, having originated more than 1 billion years ago: prior to the divergence of plants and animals. TIR domain receptors couple to at least two sets of well-characterized pathways: those leading to the activation of inhibitory κB kinase complexes/nuclear factor κB, and those leading to the activation of mitogen-activated protein kinase/AP-1/ATF-2 etc. We have been investigating these systems using a combination of expression screening methods to identify new components, and real-time green fluorescent protein-based techniques to observe execution of signalling programmes in real time. Our data reveal that there is a very large level of cell-to-cell variation in signal programme execution even in clonal populations and that at least one mechanism for dealing with this heterogeneity is the assembly of signal transduction components into large multiprotein complexes.

The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence

2000 ◽  
Vol 28 (5) ◽  
pp. 557-563 ◽  
Author(s):  
L. O'neill
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Host Defence ◽  
Mitogen Activated Protein Kinase ◽  
Adapter Proteins ◽  
Tir Domain ◽  
Gram Positive Bacteria ◽  
Th2 Cell ◽  
Mitogen Activated Protein ◽  
Bacteria And Fungi

The pro-inflammatory cytokine interleukin-1 (IL-1) signals via the Type-1 IL-1 receptor (IL-1RI), inducing an increase in the expression of many genes with roles in immunity and inflammation. The signalling pathways involve two adapter proteins, MyD88 and Tollip, which via two IL-1 receptor-associated kinases (IRAK and IRAK-2) activate transcription factors such as nuclear factor-κB and protein kinases such as p38 mitogen-activated protein kinase. A role for the low-molecular-mass G-proteins Rac, Ras and Rap in these processes has also been indicated. IL-1RI is the founder of a diverse superfamily of receptors, which all share a cytosolic domain, termed the Toll/IL-1 receptor (TIR) domain. The superfamily can be divided broadly into three subgroups. The first of these is most similar to IL-1RI and includes the receptor for IL-18 and the Th2 cell regulator T1/ST2. The second subgroup is most similar to the Drosophila melanagaster protein Toll and includes Toll-like receptor 2 (TLR2), which is required for host defence against Gram-positive bacteria and fungi, and TLR4, which is required for lipopolysaccharide responsiveness, and thus is involved in host defence against Gram-negative bacteria. There are also a number of TLRs in plants and insects, all involved in host defence. The third subgroup contains nonreceptor proteins which possess a TIR domain and are cytosolic. MyD88 is a member, and it presumably complexes with IL-1RI via a TIR-TIR interaction. The other two members are proteins encoded by the vaccinia virus, A46R and A52R, which block TIR-dependent signalling. This receptor superfamily therefore appears to play a central role in inflammation and host defence against infection, pointing to the TIR domain as a critical molecular player in the innate immune response.

scholarly journals Modulation of microtubule dynamics by a TIR domain protein from the intracellular pathogen Brucella melitensis

2011 ◽  
Vol 439 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Girish K. Radhakrishnan ◽  
Jerome S. Harms ◽  
Gary A. Splitter
Keyword(s):  
Brucella Melitensis ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Microtubule Dynamics ◽  
Innate Immune Responses ◽  
Tir Domain ◽  
Microtubule Stabilization ◽  
Loop Region ◽  
Microtubule Formation ◽  
Domain Protein

TIR (Toll/interleukin-1 receptor) domain-containing proteins play a crucial role in innate immunity in eukaryotes. Brucella is a highly infectious intracellular bacterium that encodes a TIR domain protein (TcpB) to subvert host innate immune responses to establish a beneficial niche for pathogenesis. TcpB inhibits NF-κB (nuclear factor κB) activation and pro-inflammatory cytokine secretions mediated by TLR (Toll-like receptor) 2 and TLR4. In the present study, we have demonstrated that TcpB modulates microtubule dynamics by acting as a stabilization factor. TcpB increased the rate of nucleation as well as the polymerization phases of microtubule formation in a similar manner to paclitaxel. TcpB could efficiently inhibit nocodazole- or cold-induced microtubule disassembly. Microtubule stabilization by TcpB is attributed to the BB-loop region of the TIR domain, and a point mutation affected the microtubule stabilization as well as the TLR-suppression properties of TcpB.

scholarly journals Counter-regulation in the IKK family

2011 ◽  
Vol 434 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Luke A. J. O'Neill
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Control Mechanisms ◽  
Biochemical Journal ◽  
Regulatory Feedback Loop

The human IKK [IκB (inhibitor of NF-κB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKα and IKKβ, the so-called canonical members, phosphoryate IκBα, leading to activation of the transcription factor NF-κB (nuclear factor κB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKϵ have a different substrate – IRF3 (interferon regulatory factor 3) – which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKϵ/TBK-1, which occurs via IKKα/IKKβ. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKα/IKKβ. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKϵ/TBK-1 might actually have a pro-inflammatory effect.

scholarly journals Interleukin-1 stimulates catabolism in C2C12 myotubes

2009 ◽  
Vol 297 (3) ◽  
pp. C706-C714 ◽  
Author(s):  
Wei Li ◽  
Jennifer S. Moylan ◽  
Melissa A. Chambers ◽  
Jeffrey Smith ◽  
Michael B. Reid
Keyword(s):  
Time Course ◽  
Interleukin 1 ◽  
Ring Finger ◽  
Cell Types ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Myofibrillar Protein ◽  
Mitogen Activated Protein Kinase ◽  
C2c12 Myotubes ◽  
Protein Loss

Interleukin-1 (IL-1) is an inflammatory cytokine that has been linked to muscle catabolism, a process regulated by muscle-specific E3 proteins of the ubiquitin-proteasome pathway. To address cellular mechanism, we tested the hypothesis that IL-1 induces myofibrillar protein loss by acting directly on muscle to increase expression of two critical E3 proteins, atrogin1/muscle atrophy F-box (MAFbx) and muscle RING-finger 1 (MuRF1). Experiments were conducted using mature C2C12 myotubes to eliminate systemic cytokine effects and avoid paracrine signaling by nonmuscle cell types. Time-course protocols were used to define the sequence of cellular responses. We found that atrogin1/MAFbx mRNA and MuRF1 mRNA are elevated 60–120 min after myotube exposure to either IL-1α or IL-1β. These responses are preceded by signaling events that promote E3 expression. Both IL-1 isoforms stimulate phosphorylation of p38 mitogen-activated protein kinase and stimulate nuclear factor-κB (NF-κB) signaling; I-κB levels fall and NF-κB DNA binding activity increases. Other regulators of E3 expression are unaffected by IL-1 [cytosolic oxidant activity, Forkhead-O (Foxo) activity] or respond paradoxically (AKT). Chronic exposure of C2C12 myotubes over 48 h resulted in reduced myotube width and loss of sarcomeric actin. We conclude that IL-1α and IL-1β act via an oxidant- and AKT/Foxo-independent mechanism to activate p38 MAPK, stimulate NF-κB signaling, increase expression of atrogin1/MAFbx and MuRF1, and reduce myofibrillar protein in differentiated myotubes.

scholarly journals Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence

2005 ◽  
Vol 201 (6) ◽  
pp. 1007-1018 ◽  
Author(s):  
Julianne Stack ◽  
Ismar R. Haga ◽  
Martina Schröder ◽  
Nathan W. Bartlett ◽  
Geraldine Maloney ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Virus Protein ◽  
Innate Defense ◽  
Tir Domain ◽  
Mitogen Activated Protein ◽  
Key Aspects ◽  
Tir Domains ◽  
Myeloid Differentiation Factor

Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (VV) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like–interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain–containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain–containing adaptor inducing IFN-β (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor κB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-β by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence.

scholarly journals TIRAP in the Mechanism of Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Sajjan Rajpoot ◽  
Kishore K. Wary ◽  
Rachel Ibbott ◽  
Dongfang Liu ◽  
Uzma Saqib ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protein Interactions ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Intracellular Signalling ◽  
Tir Domain ◽  
Signalling Molecules ◽  
Inflammatory Conditions ◽  
Signalling Molecule

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

scholarly journals Isoprenylcysteine Carboxyl Methyltransferase and Its Substrate Ras Are Critical Players Regulating TLR-Mediated Inflammatory Responses

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1216 ◽  
Author(s):  
Woo Seok Yang ◽  
Han Gyung Kim ◽  
Eunji Kim ◽  
Sang Yun Han ◽  
Nur Aziz ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β ◽  
Primary Response ◽  
Mitogen Activated Protein Kinase ◽  
Poly I:C ◽  
Tir Domain ◽  
Carboxyl Methyltransferase ◽  
Isoprenylcysteine Carboxyl Methyltransferase

In this study, we investigated the functional role of isoprenylcysteine carboxyl methyltransferase (ICMT) and its methylatable substrate Ras in Toll-like receptor (TLR)-activated macrophages and in mouse inflammatory disease conditions. ICMT and RAS expressions were strongly increased in macrophages under the activation conditions of TLRs by lipopolysaccharide (LPS, a TLR4 ligand), pam3CSK (TLR2), or poly(I:C) (TLR3) and in the colons, stomachs, and livers of mice with colitis, gastritis, and hepatitis. The inhibition and activation of ICMT and Ras through genetic and pharmacological approaches significantly affected the activation of interleukin-1 receptor-associated kinase (IRAK)s, tumor necrosis factor receptor associated factor 6 (TRAF6), transforming growth factor-β-activated kinase 1 (TAK1), mitogen-activated protein kinase (MAPK), and MAPK kinases (MAPKKs); translocation of the AP-1 family; and the expressions of inflammation-related genes that depend on both MyD88 and TRIF. Interestingly, the Ras/ICMT-mediated inflammatory reaction critically depends on the TIR domains of myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF). Taken together, these results suggest that ICMT and its methylated Ras play important roles in the regulation of inflammatory responses through cooperation with the TIR domain of adaptor molecules.

scholarly journals The chemotherapeutic agent DMXAA potently and specifically activates the TBK1–IRF-3 signaling axis

2007 ◽  
Vol 204 (7) ◽  
pp. 1559-1569 ◽  
Author(s):  
Zachary J. Roberts ◽  
Nadege Goutagny ◽  
Pin-Yu Perera ◽  
Hiroki Kato ◽  
Himanshu Kumar ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Advanced Phase ◽  
Novel Approach ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Mitogen Activated Protein ◽  
Signaling Axis

Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase 1 (TBK1)–interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and ∼750-fold increase in IFN-β mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor κB–dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88–, Toll–interleukin 1 receptor domain–containing adaptor inducing IFN-β–, IFN promoter-stimulator 1–, and inhibitor of κB kinase–independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of mouse macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-β expression were inhibited by salicylic acid. These findings detail a novel pathway for TBK1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs.

scholarly journals Inflammatory Cytokines IL-1β and TNF-α Regulate p75NTR Expression in CNS Neurons and Astrocytes by Distinct Cell-Type-Specific Signalling Mechanisms

ASN NEURO ◽  
2009 ◽  
Vol 1 (2) ◽  
pp. AN20090009 ◽  
Author(s):  
Soyoung Choi ◽  
Wilma J Friedman
Keyword(s):  
Inflammatory Cytokines ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Adult Brain ◽  
Mitogen Activated Protein Kinase ◽  
Neurotrophin Receptor ◽  
Cell Type ◽  
Distinct Cell Type ◽  
Tnf Α ◽  
Cell Type Specific

The p75NTR (where NTR is neurotrophin receptor) can mediate many distinct cellular functions, including cell survival and apoptosis, axonal growth and cell proliferation, depending on the cellular context. This multifunctional receptor is widely expressed in the CNS (central nervous system) during development, but its expression is restricted in the adult brain. However, p75NTR is induced by a variety of pathophysiological insults, including seizures, lesions and degenerative disease. We have demonstrated previously that p75NTR is induced by seizures in neurons, where it induces apoptosis, and in astrocytes, where it may regulate proliferation. In the present study, we have investigated whether the inflammatory cytokines IL (interleukin)-1 β and TNF- α (tumour necrosis factor- α), that are commonly elevated in these pathological conditions, mediate the regulation of p75NTR in neurons and astrocytes. We have further analysed the signal transduction pathways by which these cytokines induce p75NTR expression in the different cell types, specifically investigating the roles of the NF- κB (nuclear factor κB) and p38 MAPK (mitogen-activated protein kinase) pathways. We have demonstrated that both cytokines regulate p75NTR expression; however, the mechanisms governing this regulation are cytokine- and cell-type specific. The distinct mechanisms of cytokine-mediated p75NTR regulation that we demonstrate in the present study may facilitate therapeutic intervention in regulation of this receptor in a cell-selective manner.

Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 962-971 ◽  
Author(s):  
Yuzhen Wang ◽  
Taoyong Chen ◽  
Chaofeng Han ◽  
Donghua He ◽  
Haibo Liu ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Rab Gtpase ◽  
Type I ◽  
Tlr4 Signaling ◽  
Proinflammatory Mediators ◽  
Mitogen Activated Protein ◽  
Guanosine Triphosphatase

Abstract Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain–containing adapter, inducing interferon (IFN)-β–dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α, IL-6, nitric oxide, and IFN-β, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor κB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1–positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.

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