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 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 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.

scholarly journals Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

2004 ◽  
Vol 11 (6) ◽  
pp. 1140-1147 ◽  
Author(s):  
Hidenori Matsuzaki ◽  
Hiroshi Kobayashi ◽  
Tatsuo Yagyu ◽  
Kiyoshi Wakahara ◽  
Toshiharu Kondo ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

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 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.

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 524-531 ◽  
Author(s):  
Sarah M. Jacobs-Helber ◽  
Kwan-ho Roh ◽  
Daniel Bailey ◽  
Emmanuel N. Dessypris ◽  
John J. Ryan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Erythroid Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Murine Erythroleukemia ◽  
Necrosis Factor

Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid cells induces the activation of numerous signal transduction pathways, including the mitogen-activated protein kinase Jun-N-terminal kinase (JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha (TNF-α). EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-α, and exogenously added TNF-α induced proliferation of HCD57 cells. EPO also could induce TNF-α expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR. Addition of TNF-α activated JNK in HCD57 cells, and the activity of JNK was partially inhibited by addition of a TNF-α neutralizing antibody. Primary human and murine erythroid progenitors expressed TNF-α in either an EPO-dependent or constitutive manner. However, TNF-α had an inhibitory effect on both immature primary human and murine cells, suggestive that the proliferative effects of TNF-α may be limited to erythroleukemic cells. This study suggests a novel role for autocrine TNF-α expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-α in normal erythropoiesis.

Sign in / Sign up

Export Citation Format

Share Document