scholarly journals Anthrax Lethal Toxin Impairs CD1d-Mediated Antigen Presentation by Targeting the Extracellular Signal-Related Kinase 1/2 Mitogen-Activated Protein Kinase Pathway

2010 ◽  
Vol 78 (5) ◽  
pp. 1859-1863 ◽  
Author(s):  
Masood A. Khan ◽  
Richard M. Gallo ◽  
Randy R. Brutkiewicz
Keyword(s):  
Immune System ◽  
Protein Kinase ◽  
Bacillus Anthracis ◽  
Antigen Presentation ◽  
Specific Inhibitor ◽  
Lethal Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis and an important means by which this bacterium evades the host's immune system. In this study, we demonstrate that CD1d-expressing cells treated with LT have reduced CD1d-mediated antigen presentation. We earlier showed an important role for the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2) in the regulation of CD1d-mediated antigen presentation, and we report here that LT impairs antigen presentation by CD1d in an ERK1/2-dependent manner. Similarly, LT and the ERK1/2 pathway-specific inhibitor U0126 caused a decrease in major histocompatibility complex (MHC) class II-mediated antigen presentation. Confocal microscopy analyses revealed altered intracellular distribution of CD1d and LAMP-1 in LT-treated cells, similar to the case for ERK1/2-inhibited cells. These results suggest that Bacillus anthracis has the ability to evade the host's innate immune system by reducing CD1d-mediated antigen presentation through targeting the ERK1/2 pathway.

scholarly journals The Anti-Inflammatory Effects of Shinbaro3 Is Mediated by Downregulation of the TLR4 Signalling Pathway in LPS-Stimulated RAW 264.7 Macrophages

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Hwa-Jin Chung ◽  
Wonil Koh ◽  
Won Kyung Kim ◽  
Joon-Shik Shin ◽  
Jinho Lee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Raw 264.7 Macrophage Cells ◽  
Anti Inflammatory ◽  
Dose Dependent

Shinbaro3, a formulation derived from the hydrolysed roots of Harpagophytum procumbens var. sublobatum (Engl.) Stapf, has been clinically used in the pharamacopuncture treatment of arthritis in Korea. In the present study, Shinbaro3 inhibited NO generation in LPS-induced RAW 264.7 cells in a dose-dependent manner. Shinbaro3 also downregulated the mRNA and protein expression of inflammatory mediators in a dose-dependent manner. Three mechanisms explaining the effects of Shinbaro3 in RAW 264.7 cells were identified as follows: (1) inhibition of the extracellular signal-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase (SAPK)/c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways; (2) suppression of IκB kinase-α/β (IKK-α/β) phosphorylation and nuclear factor-kappa B (NF-κB) subunits in the NF-κB pathway, which are involved in MyD88-dependent signalling; and (3) downregulation of IFN-β mRNA expression via inhibition of interferon regulatory factor 3 (IRF3) and Janus-activated kinase 1 (JAK1)/signal transducer and activator of transcription 1 (STAT1) phosphorylation, which is involved in TRIF-dependent signalling. Shinbaro3 exerted anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophage cells through modulation of the TLR4/MyD88 pathways, suggesting that Shinbaro3 is a novel anti-inflammatory therapeutic candidate in the field of pharmacopuncture.

scholarly journals Deoxynivalenol Induces Inflammation in the Small Intestine of Weaned Rabbits by Activating Mitogen-Activated Protein Kinase Signaling

2021 ◽  
Vol 8 ◽  
Author(s):  
Pengwei Wang ◽  
Libo Huang ◽  
Wanying Yang ◽  
Quancheng Liu ◽  
Fuchang Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intestinal Inflammation ◽  
Nutrient Content ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Feeding Period ◽  
Hematopoietic Cell Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Deoxynivalenol (DON) can activate related signaling pathways and induce gastrointestinal disorders. Based on the results of previous studies, this study tried to explore the relationship between DON-induced intestinal inflammation of weaned rabbits and the ERK-p38 signaling pathway. Forty-five weaned rabbits were divided into three treatments: control, LD and HD group. All rabbits were treated with diet containing a same nutrient content, but animals in the LD and HD groups were additionally administered DON via drinking water at 0.5 and 1.5 mg/kg b.w./d, respectively. The protocol consisted of a total feeding period of 31 days, including a pre-feeding period of 7 days. Western blotting, qRT-PCR, and immunohistochemistry were applied for analysis the expression of protein and mRNA of extracellular signal-regulated kinase (ERK), p38, double-stranded RNA-activated protein kinase (PKR), and hematopoietic cell kinase (Hck) in the duodenum, jejunum, and ileum of rabbits, as well as the distribution of positive reactants. The results proved that DON intake could enhance the levels of inflammatory factors in serum and damage the intestinal structure barrier of rabbits. Meanwhile, DON addition can stimulate the protein and mRNA expression for ERK, p38, PKR, and Hck in the intestine of rabbits, especially in the duodenum, as well as expand the distribution of positive reactants, in a dose-dependent manner.

Sunitinib inhibits catecholamine synthesis and secretion in pheochromocytoma tumor cells by blocking VEGF receptor 2 via PLC-γ-related pathways

2012 ◽  
Vol 303 (8) ◽  
pp. E1006-E1014 ◽  
Author(s):  
Yuichi Aita ◽  
Kiyo-aki Ishii ◽  
Yuria Saito ◽  
Tatsuhiko Ikeda ◽  
Yasushi Kawakami ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tumor Cells ◽  
Mitogen Activated Protein Kinase ◽  
Catecholamine Secretion ◽  
Dependent Manner ◽  
Catecholamine Synthesis ◽  
Extracellular Signal Regulated Kinase ◽  
Pc 12 Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Sunitinib is an oral, small molecule multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that primarily targets vascular endothelial growth factor receptors (VEGFRs). Although sunitinib is an active agent for the treatment of malignant pheochromocytomas, it is unclear whether sunitinib acts through only antiangiogenic mechanisms or also directly targets tumor cells. We previously showed that sunitinib directly induced apoptosis of PC-12 cells. To further confirm these direct effects, we examined the effects of sunitinib on tyrosine hydroxylase (TH) (the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion in PC-12 cells and the underlying mechanisms. Sunitinib inhibited TH activity in a dose-dependent manner, and decreased TH protein levels. Consistent with this finding, sunitinib decreased TH phosphorylation at Ser31 and Ser40 and significantly decreased catecholamine secretion. VEGFR-2 knockdown attenuated these effects, including inhibition of TH activity and catecholamine secretion, suggesting that they were mediated by VEGFR-2. Sunitinib significantly decreased phospholipase C (PLC)-γ phosphorylation and subsequent protein kinase C (PKC) activity. Because Ser40 phosphorylation significantly affects TH activity and is known to be regulated by PKC, sunitinib may inhibit Ser40 phosphorylation via the VEGFR-2/PLC-γ/PKC pathway. Additionally, sunitinib markedly decreased the activity of extracellular signal-regulated kinase (ERK), but not c-Jun NH2-terminal kinase or p38 mitogen-activated protein kinase. Therefore, sunitinib may reduce TH Ser31 phosphorylation through inhibition of the VEGFR-2/PLC-γ/PKC/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/ERK pathway. Sunitinib also significantly reduced inositol 1,4,5-trisphosphate production. However, because PC-12 cells do not precisely reflect the pathogenesis of malignant cells, we confirmed the key findings in a human neuroblastoma cell line, SK-N-SH. In conclusion, sunitinib directly inhibits catecholamine synthesis and secretion in pheochromocytoma PC-12 cells.

scholarly journals Death Effector Domain Protein PEA-15 Potentiates Ras Activation of Extracellular Signal Receptor-activated Kinase by an Adhesion-independent Mechanism

2000 ◽  
Vol 11 (9) ◽  
pp. 2863-2872 ◽  
Author(s):  
Joe W. Ramos ◽  
Paul E. Hughes ◽  
Mark W. Renshaw ◽  
Martin A. Schwartz ◽  
Etienne Formstecher ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Dependent Manner ◽  
Effector Domain ◽  
Erk Activation ◽  
Death Effector Domain ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Death Effector

PEA-15 is a small, death effector-domain (DED)–containing protein that was recently demonstrated to inhibit tumor necrosis factor-α–induced apoptosis and to reverse the inhibition of integrin activation due to H-Ras. This led us to investigate the involvement of PEA-15 in Ras signaling. Surprisingly, PEA-15 activates the extracellular signal receptor-activated kinase (ERK) mitogen-activated protein kinase pathway in a Ras-dependent manner. PEA-15 expression in Chinese hamster ovary cells resulted in an increased mitogen-activated protein kinase kinase and ERK activity. Furthermore, PEA-15 expression leads to an increase in Ras guanosine 5′-triphosphate loading. PEA-15 bypasses the anchorage dependence of ERK activation. Finally, the effects of PEA-15 on integrin signaling are separate from those on ERK activation. Heretofore, all known DEDs functioned in the regulation of apoptosis. In contrast, the DED of PEA-15 is essential for its capacity to activate ERK. The ability of PEA-15 to simultaneously inhibit apoptosis and potentiate Ras-to-Erk signaling may be of importance for oncogenic processes.

scholarly journals Exercise-induced mitogen-activated protein kinase signalling in skeletal muscle

2004 ◽  
Vol 63 (2) ◽  
pp. 227-232 ◽  
Author(s):  
Yun Chau Long ◽  
Ulrika Widegren ◽  
Juleen R. Zierath
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Contraction ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Exercise Induced ◽  
Response To Exercise

Exercise training improves glucose homeostasis through enhanced insulin sensitivity in skeletal muscle. Muscle contraction through physical exercise is a physiological stimulus that elicits multiple biochemical and biophysical responses and therefore requires an appropriate control network. Mitogen-activated protein kinase (MAPK) signalling pathways constitute a network of phosphorylation cascades that link cellular stress to changes in transcriptional activity. MAPK cascades are divided into four major subfamilies, including extracellular signal-regulated kinases 1 and 2, p38 MAPK, c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 5. The present review will present the current understanding of parallel MAPK signalling in human skeletal muscle in response to exercise and muscle contraction, with an emphasis on identifying potential signalling mechanisms responsible for changes in gene expression.

scholarly journals Bacillus anthracis Spores Stimulate Cytokine and Chemokine Innate Immune Responses in Human Alveolar Macrophages through Multiple Mitogen-Activated Protein Kinase Pathways

2006 ◽  
Vol 74 (8) ◽  
pp. 4430-4438 ◽  
Author(s):  
Kaushik Chakrabarty ◽  
Wenxin Wu ◽  
J. Leland Booth ◽  
Elizabeth S. Duggan ◽  
K. Mark Coggeshall ◽  
...  
Keyword(s):  
Immune System ◽  
Bacillus Anthracis ◽  
Alveolar Macrophages ◽  
Innate Immune System ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Tnf Α ◽  
Human Alveolar Macrophages ◽  
Mitogen Activated Protein ◽  
Multiple Signaling

ABSTRACT Contact with the human alveolar macrophage plays a key role in the innate immune response to Bacillus anthracis spores. Because there is a significant delay between the initial contact of the spore with the host and clinical evidence of disease, there appears to be temporary containment of the pathogen by the innate immune system. Therefore, the early macrophage response to Bacillus anthracis exposure is important in understanding the pathogenesis of this disease. In this paper, we studied the initial events after exposure to spores, beginning with the rapid internalization of spores by the macrophages. Spore exposure rapidly activated the mitogen-activated protein kinase signaling pathways extracellular signal-regulated kinase, c-Jun-NH2-terminal kinase, and p38. This was followed by the transcriptional activation of cytokine and primarily monocyte chemokine genes as determined by RNase protection assays. Transcriptional induction is reflected at the translational level, as interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) cytokine protein levels were markedly elevated as determined by enzyme-linked immunosorbent assay. Induction of IL-6 and TNF-α, and, to a lesser extent, IL-1α and IL-1β, was partially inhibited by the blockade of individual mitogen-activated protein kinases, while the complete inhibition of cytokine induction was achieved when multiple signaling pathway inhibitors were used. Taken together, these data clearly show activation of the innate immune system in human alveolar macrophages by Bacillus anthracis spores. The data also show that multiple signaling pathways are involved in this cytokine response. This report is the first comprehensive examination of this process in primary human alveolar macrophages.

scholarly journals TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii

2004 ◽  
Vol 72 (10) ◽  
pp. 5662-5667 ◽  
Author(s):  
Nicola J. Mason ◽  
Jim Fiore ◽  
Takashi Kobayashi ◽  
Katherine S. Masek ◽  
Yongwon Choi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Wild Type ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-κB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-κB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-κB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6−/− mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6−/− mice failed to produce IL-12(p40) in response to STAg, and TRAF6−/− macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6−/− macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.

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