Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of osmolarity and compatible organic osmolytes on the phosphorylation of the MAP-kinases Erk-1 and Erk-2 and on the expression of taurine transporter (TAUT) and lipopolysaccharide (LPS)-induced nitric oxide synthetase (iNOS) was studied in RAW 264.7 mouse macrophages. Hypoosmolarity (205 mosmol/l) but not hyperosmolarity (405 mosmol/l) or challenge of the cells with betaine or taurine increased phosphorylation of Erk-1 and Erk-2. Hypoosmotic Erk-phosphorylation was blocked by the MEK-inhibitor PD098059 but was resistant to depletion of extracellular calcium and to inhibition of PLC, PKC, erbstatin-sensitive tyrosine kinases and elevation of intracellular cAMP. Hyperosmolarity stimulated Na+-dependent taurine uptake and led to an increase of TAUT mRNA levels, whereas hypoosmotic exposure diminished both and induced a rapid efflux of the osmolyte from taurine-preloaded cells. The hyperosmotic elevation of TAUT mRNA levels was antagonized upon addition of taurine but not of betaine or myo-inositol. Hyperosmolarity increased the LPS-induced iNOS expression at the mRNA and the protein level. This was suppressed by betaine but not by taurine or myo-inositol. The osmotic regulation of taurine transport and iNOS expression appeared independent of the MEK-Erk pathway and the p38MAPK.
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PMID:Compatible organic osmolytes and osmotic modulation of inducible nitric oxide synthetase in RAW 264.7 mouse macrophages. 970 50

STAT1 is an essential transcription factor for macrophage activation by IFN-gamma and requires phosphorylation of the C-terminal Ser727 for transcriptional activity. In macrophages, Ser727 phosphorylation in response to bacterial lipopolysaccharide (LPS), UV irradiation, or TNF-alpha occurred through a signaling path sensitive to the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 whereas IFN-gamma-mediated Ser727 phosphorylation was not inhibited by the drug. Consistently, SB203580 did not affect IFN-gamma-mediated, Stat1-dependent transcription but inhibited its enhancement by LPS. Furthermore, LPS, UV irradiation, and TNF-alpha caused activation of p38 MAPK whereas IFN-gamma did not. An essential role for p38 MAPK activity in STAT1 Ser727 phosphorylation was confirmed by using cells expressing an SB203580-resistant p38 MAPK. In such cells, STAT1 Ser727 phosphorylation in response to UV irradiation was found to be SB203580 insensitive. Targeted disruption of the mapkap-k2 gene, encoding a kinase downstream of p38 MAPK with a key role in LPS-stimulated TNF-alpha production and stress-induced heat shock protein 25 phosphorylation, was without a significant effect on UV-mediated Ser727 phosphorylation. The recombinant Stat1 C terminus was phosphorylated in vitro by p38MAPKalpha and beta but not by MAPK-activated protein kinase 2. Janus kinase 2 activity, previously reported to be required for IFN-gamma-mediated Ser727 phosphorylation, was not needed for LPS-mediated Ser727 phosphorylation, and activation of Janus kinase 2 did not cause the appearance of STAT1 Ser727 kinase activity. Our data suggest that STAT1 is phosphorylated at Ser727 by a stress-activated signaling pathway either through p38 MAPK directly or through an unidentified kinase downstream of p38MAPK.
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PMID:Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. 1057 Jan 80

Early events in the response of cells to lipopolysaccharide (LPS) include activation of NF-kappaB and stress-activated MAP kinase p38. Recent studies have shown that the human Toll-like receptor 2 (TLR2) mediates activation of NF-kappaB in response to commercial preparations of LPS (comLPS), membrane lipoproteins, and Gram-positive bacterial products. Here, we show that expression of TLR2 in human embryonic kidney 293 cells enabled p38 phosphorylation in response to comLPS, a synthetic bacterial lipoprotein, and B. subtilis. Activation of p38 was confirmed by an in vitro kinase assay using ATF2 as substrate and by an assay measuring activation of the downstream effector of p38, MAP kinase-activated protein kinase in cells. Thus, TLR2 initiated the signaling pathway for p38 in response to bacterial products.
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PMID:Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38. 1186 88

Neutrophil (PMN) functions can be primed for greatly increased oxidative radical release by exposure to certain agents such as lipopolysaccharide (LPS). Although a variety of signaling pathways involving both tyrosine kinases and mitogen-activated protein (MAP) kinases may be operative, the mechanisms of PMN priming are still not understood. We found that PMN priming was not achieved by treatment of cells with a very low concentration (5 ng/ml) of LPS unless additional "helper" factors were present in plasma (5%). Under these conditions, LPS induced tyrosine phosphorylation of a 38-kDa protein, which was coincident with the MAP kinase p38 action in this situation. LPS-mediated activation of p38 in human PMNs was dependent on the presence of LPS binding protein from plasma and CD14 on the surfaces of the cells. Phosphorylation of p38 was highly correlated with LPS priming of a formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN respiratory burst. Treatment of PMN with the p38-specific inhibitor SB203580 significantly attenuated the respiratory burst in cells primed by LPS and stimulated by fMLP. These results suggest that the LPS signaling pathway leading to p38 activation may be an important mechanism in regulation of PMN priming. The mediator(s) linking CD14 to p38 involves proteins that are functionally sensitive to genistein but insensitive to tyrphostin AG126 and to Src- and Syk-family kinase, protein kinase C, and phosphatidylinositol 3-kinase inhibitors. Elucidating this pathway will provide insight into possible regulation of PMN priming by LPS.
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PMID:Lipopolysaccharide-binding protein- and CD14-dependent activation of mitogen-activated protein kinase p38 by lipopolysaccharide in human neutrophils is associated with priming of respiratory burst. 1211 13

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-kappaB, mitogen-activated protein kinases, and apoptosis. LPS activated NF-kappaB by 3-4-fold in wt cells but by 9-10-fold in p60-/-, p80-/-, and p60-/- p80-/- macrophages. These results correlated with the IkappaBalpha kinase activation, which is needed for NF-kappaB activation. LPS-induced 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, p38MAPK, 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.
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PMID:Genetic deletion of the tumor necrosis factor receptor p60 or p80 sensitizes macrophages to lipopolysaccharide-induced nuclear factor-kappa B, mitogen-activated protein kinases, and apoptosis. 1269 14

We have identified a new binding partner of the TGFbeta (transforming growth factor-beta)-activated protein kinase (TAK1), termed TAB3 (TAK1-binding protein-3), which shares 48% amino acid sequence identity with TAB2. Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages, and are subject to feedback control by stress-activated protein kinase 2a (SAPK2a; also called p38alpha). The electrophoretic mobility of TAB2 and TAB3 decreases in response to these agonists or osmotic shock, and is reversed by treatment with protein phosphatase-1. The decrease in mobility of TAB3 is prevented if the cells are incubated with SB 203580 before stimulation, but treatment with SB 203580 produces forms of TAB2 with a mobility intermediate between that observed for TAB2 in unstimulated and stimulated cells. Similar results were obtained in embryonic fibroblasts from mice deficient in SAPK2a/p38alpha. Our results indicate that TAB3 is phosphorylated via the SAPK2a/p38alpha pathway, whereas TAB2 is phosphorylated at two or more sites by both an SAPK2a/p38alpha-dependent and an SB 203580-independent kinase. The SAPK2a/p38alpha-mediated phosphorylation of TAB2 and TAB3 may contribute to the SAPK2a/p38alpha-mediated feedback control of TAK1 activity that also involves the phosphorylation of TAB1. We also show that the agonist-induced activation of TAK1 complexes requires the phosphorylation of the TAK1 catalytic subunit at a serine/threonine residue(s).
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PMID:TAB3, a new binding partner of the protein kinase TAK1. 1467 75

The MAP kinase p38 plays a key role in the biosynthesis of the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and 1L-1beta. Accordingly, new pyrrolo[2, 3-]pyridine derivatives 5a-d were prepared from 2-amino-3-cyanopyrroles 3a-d via the intermediate propenylaminopyrroles 4a-d. Then the compounds 5a-d were tested for their ability to inhibit the production of TNF-alpha in vivo in rats. The most potent compounds 5a and 5b possess enhanced ability to inhibit the production of TNF-alpha stimulated with bacterial lipopolysaccharide.
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PMID:Synthesis of new pyrrolo[2, 3-b]pyridines as a potent inhibitor of tumour necrosis factor alpha. 1476 Jun 23

Macrophages undergo apoptosis as a mechanism of regulating their activation and the inflammatory reaction. Macrophages express the Corticotropin-Releasing Factor Receptor-2 (CRFR2) the endogenous agonists of which, the urocortins, are also present at the site of inflammation. We have found that urocortins induced macrophage apoptosis in a dose- and time-dependent manner via CRFR2. In contrast to lipopolysaccharide (LPS)-induced apoptosis, the pro-apoptosis pathway activated by urocortins involved the pro-apoptotic Bax and Bad proteins and not nitric oxide, JNK and p38MAPK characteristic of LPS. In conclusion, our data suggest that endogenous CRFR2 ligands exert an anti-inflammatory effect via induction of macrophage apoptosis.
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PMID:Urocortin 1 and Urocortin 2 induce macrophage apoptosis via CRFR2. 1605 39

The neurite outgrowth inhibitor protein Nogo is one of 300 proteins that contain a reticulon homology domain, which is responsible for their association with the endoplasmic reticulum. Here we have found that the Nogo-B spliceform becomes phosphorylated at Ser107 in response to lipopolysaccharide in RAW264 macrophages or anisomycin in HeLa cells. The phosphorylation is prevented by SB 203580, an inhibitor of SAPK2a (stress-activated protein kinase 2a)/p38a and SAPK2b/p38b, and does not occur in embryonic fibroblasts generated from SAPK2a/p38a-deficient mice. Nogo-B is phosphorylated at Ser107 in vitro by MAPKAP-K2 [MAPK (mitogen-activated protein kinase)-activated protein kinase-2] or MAPKAP-K3, but not by other protein kinases that are known to be activated by SAPK2a/p38a. The anisomycin-induced phosphorylation of Ser107 in HeLa cells can be prevented by 'knockdown' of MAPKAP-K2 using siRNA (small interfering RNA). Taken together, our results identify Nogo-B as a new physiological substrate of MAPKAP-K2.
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PMID:Nogo-B is a new physiological substrate for MAPKAP-K2. 1609 39

Ovulation is the complex, inflammatory-like process by which the cumulus oocyte complex (COC) is released from a mature, preovulatory follicle through a rupture site at the ovarian surface and requires expression of genes that generate and stabilize the expanded extracellular COC matrix. Gene profiling analyses of COCs at selected time intervals during ovulation revealed that many genes associated with immune related surveillance functions were also induced in cumulus cells. Specifically, cell surface signaling molecules known as pattern recognition receptors that act as sensors of the external environment important for the innate immune system to detect self from nonself or altered self are induced and/or expressed in cumulus cells as well as granulosa cells. These include the complement factor q1, CD14, and the Toll-like receptors (TLRs) 4, 8, and 9 as well as mediators of TLR activation, myeloid differentiation primary response gene 88 and interferon regulatory factor 3. COCs exposed to bacterial lipopolysaccharide exhibit enhanced phosphorylation of p38MAPK, ERK1/2 and nuclear factor-kappaB and increased expression of Il6 and Tnfa target genes, documenting that the TLR pathway is functional. Cumulus cells and granulosa cells also express the scavenger receptors CD36 and scavenger receptor type B1 and exhibited phagocytic uptake of fluorescently tagged bacterial particles. Collectively, these results provide novel evidence that cumulus cells as well as granulosa cells express innate immune related genes that may play critical roles in surveillance and cell survival during the ovulation process.
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PMID:Induced expression of pattern recognition receptors in cumulus oocyte complexes: novel evidence for innate immune-like functions during ovulation. 1693 71


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