scholarly journals p38 Mitogen-Activated Protein Kinase Controls NF-κB Transcriptional Activation and Tumor Necrosis Factor Alpha Production through RelA Phosphorylation Mediated by Mitogen- and Stress-Activated Protein Kinase 1 in Response to Borrelia burgdorferi Antigens

2006 ◽  
Vol 75 (1) ◽  
pp. 270-277 ◽  
Author(s):  
Chris M. Olson ◽  
Michael N. Hedrick ◽  
Hooman Izadi ◽  
Tonya C. Bates ◽  
Elias R. Olivera ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Transcriptional Activation ◽  
P38 Map Kinase ◽  
Phagocytic Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The interaction of Borrelia burgdorferi, the causative agent of Lyme borreliosis, with phagocytic cells induces the activation of NF-κB and the expression of proinflammatory cytokines including tumor necrosis factor alpha (TNF-α). B. burgdorferi-induced TNF-α production is also dependent on the activation of p38 mitogen-activated protein (MAP) kinase. The specific contribution of these signaling pathways to the response of phagocytic cells to the spirochete and the molecular mechanisms underlying this response remain unresolved. We now show that p38 MAP kinase activity regulates the transcriptional activation of NF-κB in response to spirochetal lysate stimulation of phagocytic cells. The regulation occurs at the nuclear level and is independent of the translocation of the transcription factor to the nucleus or its capacity to bind to specific DNA target sequences. In RAW264.7 cells, p38α MAP kinase regulates the phosphorylation of NF-κB RelA. p38 MAP kinase phosphorylates the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 in turn phosphorylates the transcriptionally active subunit of NF-κB, RelA. The repression of MSK1 expression with small interfering RNA results in reduced RelA phosphorylation and a significant decrease in the production of TNF-α in response to B. burgdorferi lysates. Overall, these results clarify the contribution of the signaling pathways that are activated in response to the interaction of spirochetes with phagocytic cells to TNF-α production. Our results situate p38 MAP kinase activity as a central regulator of the phagocytic proinflammatory response through MSK1-mediated transcriptional activation of the transcription factor NF-κB.

scholarly journals The Death Domain Kinase RIP1 Is Essential for Tumor Necrosis Factor Alpha Signaling to p38 Mitogen-Activated Protein Kinase

2003 ◽  
Vol 23 (22) ◽  
pp. 8377-8385 ◽  
Author(s):  
Thomas H. Lee ◽  
Qiaojia Huang ◽  
Sarah Oikemus ◽  
Jennifer Shank ◽  
Juan-Jose Ventura ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Map Kinase ◽  
Tumor Necrosis ◽  
P38 Map Kinase ◽  
Necrosis Factor Alpha ◽  
Kinase Activation ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The cytokine tumor necrosis factor alpha (TNF-α) stimulates the NF-κB, SAPK/JNK, and p38 mitogen-activated protein (MAP) kinase pathways by recruiting RIP1 and TRAF2 proteins to the tumor necrosis factor receptor 1 (TNFR1). Genetic studies have revealed that RIP1 links the TNFR1 to the IκB kinase (IKK) complex, whereas TRAF2 couples the TNFR1 to the SAPK/JNK cascade. In transfection studies, RIP1 and TRAF2 stimulate p38 MAP kinase activation, and dominant-negative forms of RIP1 and TRAF2 inhibit TNF-α-induced p38 MAP kinase activation. We found TNF-α-induced p38 MAP kinase activation and interleukin-6 (IL-6) production impaired in rip1 −/− murine embryonic fibroblasts (MEF) but unaffected in traf2−/− MEF. Yet, both rip1 −/− and traf2 −/− MEF exhibit a normal p38 MAP kinase response to inducers of osmotic shock or IL-1α. Thus, RIP1 is a specific mediator of the p38 MAP kinase response to TNF-α. These studies suggest that TNF-α-induced activation of p38 MAP kinase and SAPK/JNK pathways bifurcate at the level of RIP1 and TRAF2. Moreover, endogenous RIP1 associates with the MAP kinase kinase kinase (MAP3K) MEKK3 in TNF-α-treated cells, and decreased TNF-α-induced p38 MAP kinase activation is observed in Mekk3 −/− cells. Taken together, these studies suggest a mechanism whereby RIP1 may mediate the p38 MAP kinase response to TNF-α, by recruiting the MAP3K MEKK3.

scholarly journals The Streptococcal Exotoxin Streptolysin O Activates Mast Cells To Produce Tumor Necrosis Factor Alpha by p38 Mitogen-Activated Protein Kinase- and Protein Kinase C-Dependent Pathways

2003 ◽  
Vol 71 (11) ◽  
pp. 6171-6177 ◽  
Author(s):  
Michael Stassen ◽  
Christian Müller ◽  
Christoph Richter ◽  
Christine Neudörfl ◽  
Lothar Hültner ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Mast Cells ◽  
Protein Kinase ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Necrosis Factor Alpha ◽  
Kinase C ◽  
Streptolysin O ◽  
Tnf Α ◽  
Mitogen Activated Protein

ABSTRACT Streptolysin O (SLO), a major virulence factor of pyogenic streptococci, binds to cholesterol in the membranes of eukaryotic cells and oligomerizes to form large transmembrane pores. While high toxin doses are rapidly cytocidal, low doses are tolerated because a limited number of lesions can be resealed. Here, we report that at sublethal doses, SLO activates primary murine bone marrow-derived mast cells to degranulate and to rapidly induce or enhance the production of several cytokine mRNAs, including tumor necrosis factor alpha (TNF-α). Mast cell-derived TNF-α plays an important protective role in murine models of acute inflammation, and the production of this cytokine was analyzed in more detail. Release of biologically active TNF-α peaked ∼4 h after stimulation with SLO. Production of TNF-α was blunted upon depletion of protein kinase C by pretreatment of the cells with phorbol-12 myristate-13 acetate. Transient permeabilization of mast cells with SLO also led to the activation of the stress-activated protein kinases p38 mitogen-activated protein (MAP) kinase and c-jun N-terminal kinase (JNK), and inhibition of p38 MAP kinase markedly reduced production of TNF-α. In contrast, secretion of preformed granule constituents triggered by membrane permeabilization was not dependent on p38 MAP kinase or on protein kinase C. Thus, transcriptional activation of mast cells following transient permeabilization might contribute to host defense against infections via the beneficial effects of TNF-α. However, hyperstimulation of mast cells might also lead to overproduction of TNF-α, which would then promote the development of toxic streptococcal syndromes.

scholarly journals Mitogen-Activated Protein Kinase p38 Controls the Expression and Posttranslational Modification of Tristetraprolin, a Regulator of Tumor Necrosis Factor Alpha mRNA Stability

2001 ◽  
Vol 21 (19) ◽  
pp. 6461-6469 ◽  
Author(s):  
Kamal R. Mahtani ◽  
Matthew Brook ◽  
Jonathan L. E. Dean ◽  
Gareth Sully ◽  
Jeremy Saklatvala ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Rna Binding ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
The Stability ◽  
Necrosis Factor ◽  
P38 Pathway

ABSTRACT Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-α) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-α mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-α 3′ untranslated region. The p38 pathway is required for the induction of TNF-α RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-α gene expression at a posttranscriptional level.

scholarly journals Bacterial Lipopolysaccharide and Tumor Necrosis Factor Alpha Synergistically Increase Expression of Human Endothelial Adhesion Molecules through Activation of NF-κB and p38 Mitogen-Activated Protein Kinase Signaling Pathways

2001 ◽  
Vol 69 (3) ◽  
pp. 1273-1279 ◽  
Author(s):  
Hubertus P. A. Jersmann ◽  
Charles S. T. Hii ◽  
Judith V. Ferrante ◽  
Antonio Ferrante
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase ◽  
Adhesion Molecules ◽  
Cardiovascular Events ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT One of the recognized associations of bacterial infection with cardiovascular events is the activation of endothelium and upregulation of adhesion molecules. The two major proinflammatory mediators implicated in the causation of cardiovascular events, bacterial lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF), were found to cooperate to enhance the adhesive properties of endothelial cells. These caused synergistic upregulation of intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 in human umbilical vein endothelial cells as determined by flow cytometry analysis and enzyme-linked immunosorbent assay. This synergism was not due to TNF causing an upregulation of CD14 expression. Treatment with both LPS and TNF resulted in a marked increase in the translocation of NF-κB into the nucleus. The activity of p38 mitogen-activated protein kinase was also synergistically enhanced, while the activity of c-jun N-terminal kinase was increased in an additive manner. The results demonstrate that LPS and TNF act synergistically to upregulate the expression of endothelial cell adhesion molecules, possibly by amplification of signaling pathways upstream of transcription. These findings have implications for the understanding of the acceleration of atherosclerotic events seen in low-grade infections with gram-negative organisms.

scholarly journals c-Jun N-Terminal Protein Kinase 1 (JNK1), but Not JNK2, Is Essential for Tumor Necrosis Factor Alpha-Induced c-Jun Kinase Activation and Apoptosis

2004 ◽  
Vol 24 (24) ◽  
pp. 10844-10856 ◽  
Author(s):  
Jing Liu ◽  
Yuzuru Minemoto ◽  
Anning Lin
Keyword(s):  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Terminal Protein ◽  
Necrosis Factor Alpha ◽  
Kinase Activation ◽  
Jun Kinase ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Two ubiquitously expressed isoforms of c-Jun N-terminal protein kinase (JNK), JNK1 and JNK2, have shared functions and different functions. However, the molecular mechanism is unknown. Here we report that JNK1, but not JNK2, is essential for tumor necrosis factor alpha (TNF-α)-induced c-Jun kinase activation, c-Jun expression, and apoptosis. Using mouse fibroblasts deficient in either Jnk1 or Jnk2, we found that JNK1 was activated by TNF-α, whereas JNK2 activation was negligible. In addition, JNK2 interfered with JNK1 activation via its “futile” phosphorylation by upstream kinases. Consequently, expression and activation of c-Jun, which depends on JNK activity, were impaired in Jnk1 null cells but enhanced in Jnk2 null cells. TNF-α-induced apoptosis was also suppressed in Jnk1 null fibroblasts but increased in Jnk2 null cells. Thus, our results provide a molecular mechanism underlying the different biological functions of JNK isoforms.

scholarly journals Production of Tumor Necrosis Factor Alpha in Human T Lymphocytes by Staphylococcal Enterotoxin B Correlates with Toxin-Induced Proliferation and Is Regulated through Protein Kinase C

1999 ◽  
Vol 67 (12) ◽  
pp. 6611-6618 ◽  
Author(s):  
Zhengyin Yan ◽  
David C. H. Yang ◽  
Roger Neill ◽  
Marti Jett
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
Mhc Class Ii ◽  
Staphylococcal Enterotoxin B ◽  
Necrosis Factor Alpha ◽  
Kinase C ◽  
Tnf Α ◽  
Factor Alpha ◽  
Enterotoxin B ◽  
Necrosis Factor

ABSTRACT The superantigen staphylococcal enterotoxin B (SEB) simultaneously binds both the major histocompatibility complex (MHC) class II receptor on monocytes and the T-cell receptor (TCR) on T lymphocytes, resulting in a range of cell responses including induction of tumor necrosis factor alpha (TNF-α). In this study, we have used mixed cultures of human peripheral blood monocytes and lymphocytes to investigate biochemical events controlling SEB induction of TNF-α. TNF-α production induced by SEB in mixed cultures is more closely associated with T cells than with monocytes: (i) a TCR-binding-site mutant of SEB (N23F) is less active in TNF-α induction than an MHC class II receptor-binding-site mutant (F44R), and (ii) flow cytometric analysis indicated that SEB induced TNF-α production in T cells but not in monocytes. Pretreatment of cells with inhibitors of signal transduction pathways was employed to further define events in SEB-induced TNF-α production. Neither protein kinase A inhibitors nor two protein tyrosine kinase inhibitors altered SEB-induced TNF-α production. In contrast, SEB induced protein kinase C (PKC) translocation, and pretreatment of cultures with inhibitors of PKC blocked TNF-α induction. Alteration of levels of diacylglycerol (DAG), an activator of PKC, by treatment with inhibitors of phospholipase C or DAG kinase also altered SEB-induced TNF-α production. These data suggest that PKC activation plays a critical role in SEB-induced TNF-α production in human T cells.

scholarly journals Nfa34810 Facilitates Nocardia farcinica Invasion of Host Cells and Stimulates Tumor Necrosis Factor Alpha Secretion through Activation of the NF-κB and Mitogen-Activated Protein Kinase Pathways via Toll-Like Receptor 4

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Xingzhao Ji ◽  
Xiujuan Zhang ◽  
Heqiao Li ◽  
Lina Sun ◽  
Xuexin Hou ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The mechanism underlying the pathogenesis of Nocardia is not fully known. The Nfa34810 protein of Nocardia farcinica has been predicted to be a virulence factor. However, relatively little is known regarding the interaction of Nfa34810 with host cells, specifically invasion and innate immune activation. In this study, we aimed to determine the role of recombinant Nfa34810 during infection. We demonstrated that Nfa34810 is an immunodominant protein located in the cell wall. Nfa34810 protein was able to facilitate the uptake and internalization of latex beads coated with Nfa34810 protein into HeLa cells. Furthermore, the deletion of the nfa34810 gene in N. farcinica attenuated the ability of the bacteria to infect both HeLa and A549 cells. Moreover, stimulation with Nfa34810 triggered macrophages to produce tumor necrosis factor alpha (TNF-α), and it also activated mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways by inducing the phosphorylation of ERK1/2, p38, JNK, p65, and AKT in macrophages. Specific inhibitors of ERK1/2, JNK, and NF-κB significantly reduced the expression of TNF-α, which demonstrated that Nfa34810-mediated TNF-α production was dependent upon the activation of these kinases. We further found that neutralizing antibodies against Toll-like receptor 4 (TLR4) significantly inhibited TNF-α secretion. Taken together, our results indicated that Nfa34810 is a virulence factor of N. farcinica and plays an important role during infection. Nfa34810-induced production of TNF-α in macrophages also involves ERK, JNK, and NF-κB via the TLR4 pathway.

scholarly journals Activation and Mitogen-Activated Protein Kinase Regulation of Transcription Factors Ets and NF-κB in Mycobacterium-Infected Macrophages and Role of These Factors in Tumor Necrosis Factor Alpha and Nitric Oxide Synthase 2 Promoter Function

2005 ◽  
Vol 73 (10) ◽  
pp. 6499-6507 ◽  
Author(s):  
Seong-Beom Lee ◽  
Jeffrey S. Schorey
Keyword(s):  
Binding Sites ◽  
Tumor Necrosis ◽  
Promoter Activity ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase ◽  
Necrosis Factor

ABSTRACT Previous studies have shown that primary murine macrophages infected with Mycobacterium avium produced lower levels of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase 2 (NOS2) compared to cells infected with nonpathogenic Mycobacterium smegmatis. TNF-α and NOS2 levels correlated with and were dependent on the activation of mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase 1/2 (ERK1/2). To define the macrophage transcriptional responses dependent on ERK1/2 activation following a mycobacterial infection, we used RAW 264.7 cells transfected with a TNF-α or NOS2 promoter vector. We determined that macrophages infected with M. avium compared to M. smegmatis showed diminished TNF-α and NOS2 promoter activity. A more pronounced difference in promoter activity was observed when only the consensus ETS and NF-κB binding sites were used as promoters. Mutational analysis of the ETS and NF-κB binding sites present on the TNF-α and NOS2 promoters, respectively, showed that these sites were essential for a functional promoter. Moreover, the Ets/Elk but not the NF-κB transcriptional response was dependent on ERK1/2. This correlated with the requirement for ERK1/2 in TNF-α but not NOS2 promoter activity. Our data indicate that the increased Ets/Elk and NF-κB promoter activities associated with M. smegmatis-infected macrophages are responsible, at least in part, for the increased TNF-α and NOS2 production observed in these infected cells and that ERK1/2 is required for Ets/Elk activity and full TNF-α production.

scholarly journals p38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1

2005 ◽  
Vol 79 (16) ◽  
pp. 10147-10154 ◽  
Author(s):  
Davy C. W. Lee ◽  
Chung-Yan Cheung ◽  
Anna H. Y. Law ◽  
Chris K. P. Mok ◽  
Malik Peiris ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Influenza A ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Virus H5n1 ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Avian influenza A virus subtype H5N1 can infect humans to cause a severe viral pneumonia with mortality rates of more than 30%. The biological basis for this unusual disease severity is not fully understood. We previously demonstrated that in contrast to human influenza A virus subtypes including H1N1 or H3N2, the H5N1 virus associated with the “bird flu” outbreak in Hong Kong in 1997 (H5N1/97) hyperinduces proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), in primary human macrophages in vitro. To delineate the molecular mechanisms involved, we analyzed the role of transcription factor NF-κB and cellular kinases in TNF-α dysregulation. H5N1 and H1N1 viruses did not differ in the activation of NF-κB or degradation of IκB-α in human macrophages. However, we demonstrated that unlike H1N1 virus, H5N1/97 strongly activates mitogen-activated protein kinase (MAPK), including p38 MAPK and extracellular signal-regulated kinases 1 and 2. Specific inhibitors of p38 MAPK significantly reduced the H5N1/97-induced TNF-α expression in macrophages. Taken together, our findings suggest that H5N1/97-mediated hyperinduction of cytokines involves the p38 MAPK signaling pathway. These results may provide insights into the pathogenesis of H5N1 disease and rationales for the development of novel therapeutic strategies.

scholarly journals Rough Lipopolysaccharide from Brucella abortus and Escherichia coli Differentially Activates the Same Mitogen-Activated Protein Kinase Signaling Pathways for Tumor Necrosis Factor Alpha in RAW 264.7 Macrophage-Like Cells

2002 ◽  
Vol 70 (12) ◽  
pp. 7165-7168 ◽  
Author(s):  
Bruce W. Jarvis ◽  
Tajie H. Harris ◽  
Nilofer Qureshi ◽  
Gary A. Splitter
Keyword(s):  
Escherichia Coli ◽  
Brucella Abortus ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Protein Kinase Signaling ◽  
Necrosis Factor

ABSTRACT The intracellular, gram-negative pathogen Brucella abortus establishes chronic infections in host macrophages while downregulating cytokines such as tumor necrosis factor alpha (TNF-α). When producing TNF-α, Brucella abortus rough lipopolysaccharide (LPS) activates the same mitogen-activated protein kinase signaling pathways (ERK and JNK) as Escherichia coli LPS, but Brucella LPS is a much less potent agonist.

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