Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages.

Hambleton, Julie; Weinstein, Steven L.; Lem, Lawrence; DeFranco, Anthony L.

doi:10.1073/pnas.93.7.2774

Cited by 440 publications

(361 citation statements)

References 36 publications

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“…The three MAPK family members, ERK1,2, p38, and Jun Nterminal kinase, and their upstream activators are stimulated by LPS in a variety of macrophage cell types (21,27,28). The experimental work in macrophages has revealed considerable differences in MAPK responses to stimuli between primary cells and different cell lines (29).…”

Section: Discussionmentioning

confidence: 99%

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Marikovsky

Ziv

Nevo³

et al. 2003

The Journal of Immunology

185

112

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Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-α induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-α and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-α, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-α levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-α serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.

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Section: Discussionmentioning

confidence: 99%

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Marikovsky

Ziv

Nevo³

et al. 2003

The Journal of Immunology

185

112

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“…In mammalian cells, TLR2, TLR3 and TLR4 are known to share a common pro-inflammatory signal transduction pathway leading to the nuclear translocation of the transcription factor nuclear factor (NF)-‹ B and transcription of various genes [8][9][10]. Additionally, LPS and dsRNA are reported to induce signaling via c-Jun N-terminal kinase (JNK) [11,12], p38 mitogen-activated protein kinase (p38 MAPK) [12,13] and extracellular signal-regulated kinase 1/2 (ERK1/2) [14,15].…”

Section: Introductionmentioning

confidence: 99%

Toll‐like receptor stimulation induces airway hyper‐responsiveness to bradykinin, an effect mediated by JNK and NF‐κB signaling pathways

et al. 2004

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Airway infections induce hyper-responsiveness in asthmatic patients. Toll-like receptors (TLR) mediate inflammatory responses to microbes. Occurrence and effects of TLR2, TLR3 and TLR4 were examined in a mouse organ culture model of asthma focusing on the smooth muscle responses to bradykinin. TLR2, TLR3 and TLR4 mRNA, and TLR2 and TLR4 immunoreactivity were detected in the tracheal muscle layer. Tracheal organ culture for 1 or 4 days with lipopolysaccharide (LPS; TLR2/4 agonist) or polyinosinic polycytidylic acid (poly-I-C; TLR3 agonist) enhanced bradykinin-and [des-Arg 9 ]-bradykinin-induced contractions. Simultaneous LPS and poly-I-C treatment resulted in synergistic enhancement of bradykinin-induced contraction. In carbachol-pre-contracted segments TLR stimulation induced less potent relaxations to bradykinin and [des-Arg 9 ]-bradykinin. The LPS and poly-I-C enhancement of bradykinin-induced contraction was inhibited by the transcriptional inhibitor actinomycin-D, dexamethasone, the proteasome inhibitor MG-132 and the c-Jun Nterminal kinase (JNK) inhibitor SP600125. LPS and poly-I-C induced translocation of NF-‹ B p65 to the nucleus and up-regulation of kinin B 1 and B 2 receptor mRNA. In summary, TLR2, TLR3 and TLR4 are expressed in the mouse tracheal smooth muscle. Costimulation of these receptors results in NF-‹ B-and JNK-mediated transcription of B 1 and B 2 receptor, inducing hyper-responsiveness to bradykinin.

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“…These results demonstrate that the presence of TNF receptors suppressed LPS-induced activation of macrophages. (22). To explore the specific role of TNF receptors in LPS-induced JNK activation, we treated the wt macrophage cell line and its TNF receptordeficient variants with LPS (0.1 g/ml) for various times, prepared whole cell extracts, immunoprecipitated the JNK, and analyzed them for JNK by immune complex kinase assay.…”

Section: Fig 1 Deletion Of Tnf Receptors Enhances Lps-induced Activmentioning

confidence: 99%

“…LPS is then transferred to the transmembrane signaling receptor toll-like receptor 4 (TLR4) and its accessory protein MD2 (8 -10). LPS stimulation of human monocytes activates several intracellular signaling pathways that include the I B kinase (IKK)-NF-B pathway (11)(12)(13)(14)(15) and three mitogen-activated protein kinase (MAPK) pathways: p42/p44 MAPK /extracellular signal-regulated kinases 1 and 2 (ERK1/2) (16 -21), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) (22), and p38 MAPK (23,24).…”

mentioning

confidence: 99%

Genetic Deletion of the Tumor Necrosis Factor Receptor p60 or p80 Sensitizes Macrophages to Lipopolysaccharide-induced Nuclear Factor-κB, Mitogen-activated Protein Kinases, and Apoptosis

Takada

Aggarwal

2003

Journal of Biological Chemistry

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Whether deletion of tumor necrosis factor (TNF) receptor 1 or 2 affects lipopolysaccharide (LPS)-mediated signaling is not understood. In this report, we used macrophages derived from wild type (wt) mice and from mice null for the type 1 receptor (p60 ؊/؊ ), the type 2 receptor (p80 ؊/؊ ), or both (p60 ؊/؊ p80 ؊/؊ ) to investigate the effect of these receptors on LPS-mediated activation of NF-B, mitogen-activated protein kinases, and apoptosis. LPS activated NF-B by 3-4-fold in wt cells but by 9 -10-fold in p60 ؊/؊ , p80 ؊/؊ , and p60 ؊/؊ p80 ؊/؊ macrophages. These results correlated with the I B␣ kinase activation, which is needed for NF-B activation. LPSinduced cyclooxygenase-2 and inducible NO synthase proteins and NO production were maximum in p60 ؊/؊ p80 ؊/؊ macrophages and minimum in wt cells. LPS activated C-Jun N-terminal kinase, p38 MAPK , and extracellular signal-regulated kinase in wt cells, but the levels were much higher in p60 ؊/؊ , p80 ؊/؊ , and p60 ؊/؊ p80 ؊/؊ cells. LPS-induced cytotoxicity, poly(ADP-ribose) polymerase cleavage, and annexin V staining were also highest in p60 ؊/؊ p80 ؊/؊ cells and lowest in wt cells. The difference in LPS signaling was unrelated to the expression of LPS receptors, CD14, or toll-like receptor 4. Overall, our studies indicate that deletion of either of the TNF receptors sensitizes the macrophages to LPS and provide evidence for cross-talk between TNF and LPS signaling.It has been known for decades that Gram-negative bacteria and their component lipopolysaccharides (LPS) 1 have antitumor properties in vivo and that these properties are mediated primarily through production of tumor necrosis factor (TNF) (1, 2). LPS or endotoxin is a glycolipid and is an integral component of the outer membrane of Gram-negative bacteria.LPS mediates a number of biologic manifestations of sepsis, including fever, hypotension, multiple organ failure, shock, and death (3). These effects of endotoxin are believed to result from an uncontrolled production of proinflammatory cytokines produced by cells of the reticuloendothelial system, particularly macrophages. LPS-dependent macrophage activation results in the release of TNF, IL-1, IL-6, IL-8, IL-10, and IL-12.LPS interacts with most cells through CD14, a 55-kDa glycosylphosphatidylinositol-anchored protein expressed on the surface of monocytes and neutrophils (4, 5). The binding of LPS to CD14 is enhanced by the LPS-binding protein present in the serum (5, 6). Mice that lack the CD14 gene show resistance to LPS-induced shock (7). LPS is then transferred to the transmembrane signaling receptor toll-like receptor 4 (TLR4) and its accessory protein MD2 (8 -10). LPS stimulation of human monocytes activates several intracellular signaling pathways that include the I B kinase (IKK)-NF-B pathway (11-15) and three mitogen-activated protein kinase (MAPK) pathways: p42/p44 MAPK /extracellular signal-regulated kinases 1 and 2 (ERK1/2) (16 -21), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) (22), and p38 MAPK (23,24).Both LPS ...

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Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages.

Abstract: Activation of macrophages by bacterial lipopolysaccharide (LPS)

Cited by 440 publications

References 36 publications

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Toll‐like receptor stimulation induces airway hyper‐responsiveness to bradykinin, an effect mediated by JNK and NF‐κB signaling pathways

Genetic Deletion of the Tumor Necrosis Factor Receptor p60 or p80 Sensitizes Macrophages to Lipopolysaccharide-induced Nuclear Factor-κB, Mitogen-activated Protein Kinases, and Apoptosis

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