LPS- and LTA-Induced Expression of IL-6 and TNF-αin Neonatal and Adult Blood: Role of MAPKs and NF-κB

As nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) seem to be critical mediators in the inflammatory response, we studied the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) on (a) the activation of NF-κB and MAPKs and (b) the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) with or without the specific inhibitors of these intracellular signal transduction pathways in neonatal cord and adult blood. TNF-αand IL-6 concentrations showed a sharp increase in the supernatants of cord and adult whole blood after stimulation. TNF-αconcentrations were significantly higher, whereas IL-6 concentrations were tendentially lower in adult blood after stimulation. Stimulation with LPS or LTA resulted in a significantly decreased activation of p38 MAPK in neonatal compared with adult blood. Although LTA failed to induce additional ERK1/2 phosphorylation, LPS stimulation mediated the moderately increased levels of activated ERK1/2 in neonatal monocytes. The addition of the p38 MAPK inhibitor SB202190 significantly decreased IL-6 and TNF-αproduction upon LPS or LTA stimulation. Furthermore, the inhibition of ERK1/2 was able to reduce LPS-stimulated TNF-αproduction in neonatal blood. We conclude that p38 MAPK as well as ERK1/2 phosphorylation is crucially involved in LPS activation and could explain the differences in early cytokine response between neonatal and adult blood.

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Inhibition of LPS-Induced Activation of Coagulation by p38 MAPK Inhibitor

ISRN Hematology ◽

10.5402/2012/762614 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 5

Author(s):

Lutz Koch ◽

Stefan Hofer ◽

Markus A. Weigand ◽

David Frommhold ◽

Johannes Poeschl ◽

...

Keyword(s):

P38 Mapk ◽

Sandwich Elisa ◽

Mitogen Activated Protein Kinase ◽

Toll Like Receptor ◽

Inhibitory Effects ◽

Coagulation Activation ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

During Gram-negative sepsis, lipopolysaccharide (LPS) activates toll-like receptor (TLR) 4 and induces complex responses of immune system and coagulation. However, the underlying LPS signalling mechanism on coagulation activation remains complex. To determine the role of the intracellular signalling factors p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and c-Jun N-terminal kinase (JNK) in the procoagulant response to LPS, coagulation process of human whole blood exposed to specific inhibitors was measured by thrombelastography. Samples were stimulated with LPS (100 μg/mL) after preincubation with BAY117082 (specific NF-κB inhibitor), SP600125 (specific JNK inhibitor), SB203580 (specific p38 MAPK inhibitor), or vehicle. SB203580 strongly inhibited LPS-induced coagulation activation, whereas BAY117082 and SP600125 showed no significant effect. Activation of p38 MAPK, NF-κB, and JNK and respective inhibitory effects were confirmed by Multi-Target Sandwich ELISA. In conclusion, activation of p38 MAPK is crucial for early LPS-induced activation of coagulation.

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Role of early- or late-phase activation of p38 mitogen-activated protein kinase induced by tumour necrosis factor-alpha or 2,4-dinitrochlorobenzene during maturation of murine dendritic cells

Immunology ◽

10.1046/j.1365-2567.2003.01746.x ◽

2003 ◽

Vol 110 (3) ◽

pp. 322-328 ◽

Cited By ~ 16

Author(s):

Norifumi Iijima ◽

Yoshiki Yanagawa ◽

Kazunori Onoe

Keyword(s):

Dendritic Cells ◽

Tumour Necrosis ◽

Late Phase ◽

Tumour Necrosis Factor Alpha ◽

Mitogen Activated Protein Kinase ◽

Necrosis Factor Alpha ◽

Mitogen Activated Protein ◽

Factor Alpha ◽

Necrosis Factor

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

Journal of Virology ◽

10.1128/jvi.79.16.10147-10154.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10147-10154 ◽

Cited By ~ 97

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.

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