scholarly journals LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

2003 ◽  
Vol 198 (7) ◽  
pp. 1043-1055 ◽  
Author(s):  
Katherine A. Fitzgerald ◽  
Daniel C. Rowe ◽  
Betsy J. Barnes ◽  
Daniel R. Caffrey ◽  
Alberto Visintin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Tlr4 Signaling ◽  
Tir Domain ◽  
Toll Receptor ◽  
Inducible Protein ◽  
Myeloid Differentiation Factor ◽  
Lps Signaling ◽  
Interferon Inducible Protein

Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-β (TRIF)–related adaptor molecule (TRAM) is the fourth TIR domain–containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-κB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-α/β, regulated on activation, normal T cell expressed and secreted (RANTES), and γ interferon–inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor–like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS.

scholarly journals Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wenliang Su ◽  
Huan Cui ◽  
Danning Wu ◽  
Jiawen Yu ◽  
Lulu Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
High Mobility ◽  
Adaptor Protein ◽  
Immunofluorescent Staining ◽  
Inhibitory Peptide ◽  
Tlr4 Signaling ◽  
Innate Immunity Pathway ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor

Abstract Background As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure. Methods The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain. Results Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH. Conclusions HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.

scholarly journals Inhibitory Role of an Aeromonas hydrophila TIR Domain Effector in Antibacterial Immunity by Targeting TLR Signaling Complexes in Zebrafish

2021 ◽  
Vol 12 ◽  
Author(s):  
Huai-ping Tang ◽  
Chen Huang ◽  
Chong-bin Hu ◽  
Hao Li ◽  
Tong Shao ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Aeromonas Hydrophila ◽  
Protein Complexes ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Therapeutic Interventions ◽  
Death Domain ◽  
Tir Domain ◽  
Myeloid Differentiation Factor

The Toll/interleukin-1 receptor (TIR) domain is a structural unit responsible for the assembly of signal protein complexes in Toll-like receptor (TLR) and interleukin-1 receptor signaling pathways. TIR domain homologs are found in a considerable number of bacteria and enhance bacterial infection and survival in host organisms. However, whether TIR domain homologs exist in Aeromonas hydrophila, a ubiquitous waterborne bacterium in aquatic environments, remains poorly understood. In this study, a TIR domain protein (TcpAh) was identified from A. hydrophila JBN2301. TIR domain of TcpAh is highly homologous to the counterpart domains in TLRs and myeloid differentiation factor 88 (MyD88). The zebrafish infected with mutant A. hydrophila with tcpAh deletion had a remarkably lower mortality than those infected with the wild-type strain. This result suggests that TcpAh is a crucial virulence factor for A. hydrophila infection. TcpAh exhibited a strong ability to associate with MyD88, tumor necrosis factor receptor-associated factor 3 (TRAF3) and TRAF-associated NF-κB activator-binding kinase 1 (TBK1) in TIR–TIR, TIR–Death domain (DD), and other alternative interactions. This finding suggests that TcpAh extensively interferes with MyD88 and TIR domain-containing adapter inducing interferon (IFN)-β (TRIF) signaling pathways downstream of TLRs. Consequently, CD80/86 expression was suppressed by TcpAh via attenuating TLR-stimulated NF-κB activation, which ultimately led to the impairment of the major costimulatory signal essential for the initiation of adaptive humoral immunity against A. hydrophila infection. We believe that this study is the first to show a previously unrecognized mechanism underlying A. hydrophila evades from host antibacterial defense by intervening CD80/86 signal, which bridges innate and adaptive immunity. The mechanism will benefit the development of therapeutic interventions for A. hydrophila infection and septicemia by targeting TcpAh homologs.

scholarly journals LPS-mediated inflammation in cardiovascular diseases

2018 ◽  
pp. 14-22
Author(s):  
И.В. Федотов ◽  
Н.Ю. Русецкая ◽  
Е.В. Бобылева ◽  
В.Б. Бородулин
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Signaling Pathways ◽  
Active Oxygen Species ◽  
Atherosclerotic Lesion ◽  
Adaptor Protein ◽  
Bacterial Cells ◽  
Tlr4 Signaling ◽  
Atp Production ◽  
Atherosclerotic Process

Возникновение и развитие сердечной недостаточности как проявление атеросклеротического процесса или первичного поражения кардиомиоцитов при кардиомиопатиях может быть связано с накоплением в крови эндотоксинов - компонентов бактериальных клеток, в частности липополисахарида (ЛПС) клеточной стенки грамотрицательных бактерий. ЛПС при связывании с TOLL-подобными рецепторами (TLR) запускают сигнальные пути, вследствие чего происходит синтез провоспалительных цитокинов, выработка активных форм кислорода и азота, развитие окислительного стресса и воспаления в месте атеросклеротического поражения. Активация ЛПС-TLR4-сигнальных путей в тромбоцитах способствует развитию тромбоза. При ишемии миокарда и сердечной недостаточности наблюдается дисбаланс между окислительным стрессом и антиоксидантными механизмами. Миокард имеет эндогенные восстановительные механизмы, в том числе системы тиоредоксина (Trx) и глутатиона (GSH), которые направлены на удаление активных форм кислорода и восстановление окисленных белков, часть из которых участвует в ЛПС-TLR4-сигнальных путях. Например, GSH способен модифицировать адапторный белок MyD88, а Trx является прямым ингибитором протеинкиназы ASK1, способствуя подавлению проапоптотических сигнальных путей во время острого воспаления в кардиомиоцитах. Кроме того, Trx предотвращает дисфункцию митохондрий, увеличивает производство АТФ, ингибирует апоптоз и тем самым оказывает кардиопротекторное действие. Emergence and development of heart failure as a manifestation of atherosclerotic process or primary lesion to cardiomyocytes in cardiomyopathies can be caused by blood accumulation of endotoxins, components of bacterial cells, such as lipopolysaccharide (LPS) of gram-negative bacterial cell wall. LPS binding to TOLL-like receptors (TLR) triggers signaling pathways to induce synthesis of pro-inflammatory cytokines, production of reactive oxygen and nitrogen species, and development of oxidative stress and inflammation at the site of atherosclerotic lesion. Activation of LPS-TLR4-signaling pathways in platelets contributes to development of thrombosis. An imbalance between oxidative stress and antioxidant mechanisms is observed in myocardial ischemia and heart failure. The myocardium has endogenous restorative mechanisms, including the systems of thioredoxin (Trx) and glutathione (GSH) designed for removing active oxygen species and reducing oxidized proteins, some of which are involved in LPS-TLR4 signaling pathways. For example, GSH is able to modify the adaptor protein MyD88 while Trx is a direct inhibitor of protein kinase ASK1, to facilitate suppression of proapoptotic signaling pathways during acute inflammation in cardiomyocytes. In addition, Trx prevents mitochondrial dysfunction, increases ATP production, inhibits apoptosis and, thereby, exerts a cardioprotective effect.

scholarly journals Porphyromonasgingivalis Lipopolysaccharide Antagonizes Escherichiacoli Lipopolysaccharide at Toll-Like Receptor 4 in HumanEndothelialCells

2003 ◽  
Vol 71 (12) ◽  
pp. 6799-6807 ◽  
Author(s):  
Stephen R. Coats ◽  
Robert A. Reife ◽  
Brian W. Bainbridge ◽  
Thu-Thao T. Pham ◽  
Richard P. Darveau
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Toll Like Receptor ◽  
Human Endothelial Cells ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
E Coli ◽  
Signaling Complex

ABSTRACT E. coli lipopolysaccharide (LPS) induces cytokine and adhesion molecule expression via the toll-like receptor 4 (TLR4) signaling complex in human endothelial cells. In the present study, we investigated the mechanism by which Porphyromonas gingivalis LPS antagonizes E. coli LPS-dependent activation of human endothelial cells. P. gingivalis LPS at 1 μg/ml inhibited both E. coli LPS (10 ng/ml) and Mycobacterium tuberculosis heat shock protein (HSP) 60.1 (10 μg/ml) stimulation of E-selectin mRNA expression in human umbilical vein endothelial cells (HUVEC) without inhibiting interleukin-1 beta (IL-1β) stimulation. P. gingivalis LPS (1μ g/ml) also blocked both E. coli LPS-dependent and M. tuberculosis HSP60.1-dependent but not IL-1β-dependent activation of NF-κB in human microvascular endothelial (HMEC-1) cells, consistent with antagonism occurring upstream from the TLR/IL-1 receptor adaptor protein, MyD88. Surprisingly, P. gingivalis LPS weakly but significantly activated NF-κB in HMEC-1 cells in the absence of E. coli LPS, and the P. gingivalis LPS-dependent agonism was blocked by transient expression of a dominant negative murine TLR4. Pretreatment of HUVECs with P. gingivalis LPS did not influence the ability of E. coli LPS to stimulate E-selectin mRNA expression. Taken together, these data provide the first evidence that P. gingivalis LPS-dependent antagonism of E. coli LPS in human endothelial cells likely involves the ability of P. gingivalis LPS to directly compete with E. coli LPS at the TLR4 signaling complex.

A 3-styrylchromone converted from trimebutine 3D pharmacophore possesses dual suppressive effects on RAGE and TLR4 signaling pathways

2021 ◽  
Vol 566 ◽  
pp. 1-8
Author(s):  
Miwa Okazawa ◽  
Takahiro Oyama ◽  
Hideaki Abe ◽  
Hiroaki Yamazaki ◽  
Atsushi Yoshimori ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tlr4 Signaling ◽  
3D Pharmacophore

scholarly journals Targeted Expression of the Class II Phosphoinositide 3-Kinase in Drosophila melanogaster Reveals Lipid Kinase-Dependent Effects on Patterning and Interactions with Receptor Signaling Pathways

2004 ◽  
Vol 24 (2) ◽  
pp. 796-808 ◽  
Author(s):  
Lindsay K. MacDougall ◽  
Mary Elizabeth Gagou ◽  
Sally J. Leevers ◽  
Ernst Hafen ◽  
Michael D. Waterfield
Keyword(s):  
Drosophila Melanogaster ◽  
Signaling Pathways ◽  
Egf Receptor ◽  
Adaptor Protein ◽  
Class Ii ◽  
Notch Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Class I ◽  
Wing Venation ◽  
Receptor Signaling

ABSTRACT Phosphoinositide 3-kinases (PI3Ks) can be divided into three distinct classes (I, II, and III) on the basis of their domain structures and the lipid signals that they generate. Functions have been assigned to the class I and class III enzymes but have not been established for the class II PI3Ks. We have obtained the first evidence for a biological function for a class II PI3K by expressing this enzyme during Drosophila melanogaster development and by using deficiencies that remove the endogenous gene. Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling. These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor. A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk. Drk may thus be important for the localization of PI3K_68D, allowing it to modify signaling pathways downstream of cell surface receptors. The phenotypes obtained are markedly distinct from those generated by expression of the Drosophila class I PI3K, which affects growth but not pattern formation.

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