Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocytic cells constitute an important defense mechanism against invading pathogens by recognizing conserved pathogens components. The recognition leads to activation of intracellular pathways involving nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPK), such as the c-Jun NH2-terminal kinase (JNK), and p38. We show that in vitro infection with Francisella tularensis results in activation of NF-kappaB, phosphorylation of p38 and c-Jun, and secretion of TNF-alpha in adherent mouse peritoneal cells, in the mouse macrophage-like cell line J774A.1, in the human macrophage cell line THP-1, and in human peripheral blood monocytic cells. This occurred after infection with the human live vaccine strain, F. tularensis LVS or a mutant strain denoted deltaiglC, which lacks expression of a 23-kDa protein, or after addition of killed F. tularensis LVS. Addition of purified F. tularensis LPS resulted in no discernible effects on the cells. When the effects were followed up to 5 h, activation persisted in cultures with killed bacteria or infected with the deltaiglC strain. In contrast, the signal transduction activation and secretion of TNF-alpha were down-regulated within the 5h period in mouse peritoneal cells, J774 cells or human peripheral blood mononuclear cells infected with F. tularensis LVS. Together, the results suggest that infection with live F. tularensis LVS bacteria leads to a rapid induction of a proinflammatory response in mouse and human cells but after internalization of bacteria, this response is completely or partly down-regulated in most cell types. This down-regulation does not occur when cells are infected with the mutant deltaiglC.
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PMID:Francisella tularensis LVS initially activates but subsequently down-regulates intracellular signaling and cytokine secretion in mouse monocytic and human peripheral blood mononuclear cells. 1592 73

Glutathione S-transferase P1(GSTP1) plays an important role in the detoxification and xenobiotics metabolism. Here, we show that GSTP1 is also involved in LPS (lipopolysaccharide)-induced inflammatory response. GSTP1 expression, determined at the transcription and translation levels, were upregulated by the LPS stimulation in RAW264.7 macrophage-like cells. GSTP1 inhibited LPS-induced mitogen-activated protein kinases MAPKs including ERK, JNK and p38 as well as NF-kappaB activation dose- and time-dependently in transient transfected and stable transfected cells. Moreover this inhibition of the signaling pathways resulted in the decrease of tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) synthesis. These data suggest that the GSTP1 prevents LPS-induced excessive production of pro-inflammatory factors and plays an anti-inflammatory role in response to LPS.
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PMID:Regulation of lipopolysaccharide-induced inflammatory response by glutathione S-transferase P1 in RAW264.7 cells. 1602 7

The molecular mechanisms for increased risk of bacterial pneumonia in HIV+ persons remain incompletely understood. Recognizing the critical role of Toll-like receptor (TLR) signaling in host defense, this study showed that human U937 macrophage stimulation by the TLR4-specific ligand, lipid A (biologically active component of bacterial LPS), promoted TNF-alpha release through extracellular regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase phosphorylation. In contrast, HIV+ U1 macrophages had significantly reduced TNF-alpha release (despite preserved TLR4 expression) and reduced ERK1/2 phosphorylation, whereas TNF-alpha release was intact via a TLR4-independent pathway. In HIV+ U1 cells, reduced ERK1/2 phosphorylation was not due to reduced upstream MEK1/2 activation, but was associated with a reciprocal induction of MAP kinase phosphatase-1 (MKP-1). HIV nef protein was sufficient to reduce TNF-alpha release and induce MKP-1 in healthy macrophages. Pharmacologic inhibition of endogenous cellular phosphatases increased ERK1/2 phosphorylation and partially restored TLR4-mediated TNF-alpha release in HIV+ macrophages. Furthermore, targeted gene silencing of MKP-1 partially restored lipid A-mediated TNF-alpha release in HIV+ U1 cells. Similar results were observed using clinically relevant human alveolar macrophages, comparing healthy to asymptomatic HIV+ persons at clinical risk for bacterial pneumonia. Thus, reduced TLR4-mediated TNF-alpha release through altered ERK1/2 regulation by HIV may impair an effective innate immune response to bacterial challenge. Inhibition of cellular phosphatases may serve as a potential therapeutic target in the management of bacterial pneumonia in HIV+ persons.
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PMID:HIV impairs TNF-alpha release in response to Toll-like receptor 4 stimulation in human macrophages in vitro. 1610 84

Exposure of phagocytic cells to bacterial endotoxin (lipopolysaccharide; LPS) or inflammatory cytokines confers antiapoptotic survival signals; however, in the absence of the appropriate stimulus, monocytes are programmed to undergo apoptosis. Macrophage survival may thus influence inflammatory and immune responses and susceptibility to microbial pathogens. Herein, we demonstrate that LPS and the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), enhance monocytic cell survival through the induction of the antiapoptotic c-IAP2 gene in a human promonocytic THP-1 cell line. We also investigated the role of upstream signaling molecules including the mitogen-activated protein kinases, phosphatidylinositol 3-kinase, and the calcium signaling pathways in the regulation of c-IAP2 expression and eventual survival of monocytic cells. Our results suggest that LPS and TNF-alpha-induced c-IAP2 expression was regulated by calmodulin (CaM) through the activation of calmodulin-dependent protein kinase-II (CaMKII). In addition, CaM and CaMKII regulated c-IAP2 expression in LPSand TNF-alpha-stimulated cells through NF-kappaB activation. Moreover, the CaM/CaMKII pathway also regulated LPS- and TNF-alpha-mediated inhibition of apoptosis in these cells. Taken together, these results suggest that LPS- and TNF-alpha-induced c-IAP2 expression and its associated antiapoptotic survival signals in THP-1 cells are regulated selectively by CaM/CaMKII through NF-kappaB activation.
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PMID:Distinct role of calmodulin and calmodulin-dependent protein kinase-II in lipopolysaccharide and tumor necrosis factor-alpha-mediated suppression of apoptosis and antiapoptotic c-IAP2 gene expression in human monocytic cells. 2231 81

Ligation of Toll-like receptors (TLR) on macrophages induces cytokines and mediators important for the control of pathogens. Macrophage activation has to be tightly controlled to prevent hyper-inflammation. Accordingly, the hallmarks of TLR-triggered signaling, nuclear translocation of NF-kappaB and phosphorylation of mitogen-activated protein kinases (MAPK), are transient events. We have mined microarray datasets for changes in the expression of phosphatases in resting and TLR-activated macrophages. Several members of the dual-specificity phosphatases (DUSP) were induced upon triggering TLR4 with LPS. Up-regulation of DUSP1 mRNA was transient after stimulation with LPS alone, but addition of the immunosuppressive cytokine IL-10 resulted in robust, continued DUSP1 expression. IL-10 also synergized with the anti-inflammatory glucocorticoid dexamethasone in the induction of DUSP1 mRNA expression in activated macrophages, as well as in the inhibition of IL-6 and IL-12 production. Increased expression of DUSP1 in IL-10-treated activated macrophages was correlated with a faster down-regulation of p38 MAPK activation. Thus, these data suggest an operational link between IL-10 and inhibition of p38 MAPK via sustained expression of DUSP1.
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PMID:Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. 1618 16

NO production by macrophages in response to lipoteichoic acid (LTA) and a synthetic lipopeptide (Pam3CSK4) was investigated. LTA and Pam3CSK4 induced the production of both TNF-alpha and NO. Inhibitors of platelet-activating factor receptor (PAFR) blocked LTA- or Pam3CSK4-induced production of NO but not TNF-alpha. Jak2 tyrosine kinase inhibition blocked LTA-induced production of NO but not TNF-alpha. PAFR inhibition blocked phosphorylation of Jak2 and STAT1, a key factor for expressing inducible NO synthase. In addition, LTA did not induce IFN-beta expression, and p38 mitogen-activated protein serine kinase was necessary for LTA-induced NO production but not for TNF-alpha production. These findings suggest that Gram-positive bacteria induce NO production using a PAFR signaling pathway to activate STAT1 via Jak2. This PAFR/Jak2/STAT1 signaling pathway resembles the IFN-beta, type I IFNR/Jak/STAT1 pathway described for LPS. Consequently, Gram-positive and Gram-negative bacteria appear to have different but analogous mechanisms for NO production.
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PMID:Lipoteichoic acid-induced nitric oxide production depends on the activation of platelet-activating factor receptor and Jak2. 1636 52

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.
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PMID:N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. 1646 52

Engaging mammalian Toll-like receptors (TLRs) activate both the NF-kappaB and mitogen-activated protein kinase signaling pathways. Here we establish that mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands. Despite rescuing TLR-dependent ERK activation in nfkb1(-/-) bone marrow-derived macrophages by using an estrogen receptor-regulated version of the mitogen-activated protein 3 kinase, c-Raf (Raf:ER), CpG or LPS induction of IL-10 was only partially restored in nfkb1(-/-) cells expressing Raf:ER, a finding consistent with NF-kappaB1 regulating IL-10 by a combination of ERK-independent and -dependent mechanisms. Collectively, our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells.
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PMID:Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. 1648 70

CKBM is an herbal formula composed of five Chinese medicinal herbs (Panax ginseng, Schisandra chinensis, Fructus crataegi, Ziziphus jujuba and Glycine max) supplemented with processed Saccharomyces cerevisiae. It has been demonstrated that CKBM is capable of triggering the release of IL-6 and TNFalpha from human peripheral blood mononuclear cells. In this report, T-lymphocytic Sup-T1 cells and B-lymphocytic Ramos cells were utilized as cellular models to investigate how CKBM regulates intracellular signaling as well as the production of cytokines. CKBM stimulated the three major subgroups of mitogen-activated protein kinase (i.e. ERK, JNK and p38) in Sup-T1 cells, but only triggered the activation of ERK and p38 in Ramos cells. The induction of mitogen-activated protein kinases (MAPK) activations varied with the duration of treatment, as well as with the dosage of CKBM. In terms of cytokine production, treatment of CKBM alone did not trigger the release of IL-1beta and IFNgamma, but it suppressed the LPS-induced IFNgamma production from both Sup-T1 cells and Ramos cells. In view of the therapeutic effects of traditional Chinese medicines in inflammatory and autoimmune disorders, the results suggest that CKBM may exhibit its immuno-modulatory effects by regulating intracellular signaling as well as cytokine production in different lymphocytic cell types.
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PMID:CKBM stimulates MAPKs but inhibits LPS-induced IFN-gamma in lymphocytes. 1677 8

Infection of the maternal vaginal tract is one of the single most important antecedents of premature labor. We have hypothesized that the abundant local synthesis of pro-inflammatory cytokines that occurs during infection may disrupt the delicate "immunological cross-talk" that must occur between maternal and fetal tissues in order to carry pregnancy to term. These experiments were undertaken as part of a larger study directed at testing that hypothesis. We prepared primary cultures of human trophoblasts from term placentas. Cell cultures were stimulated with conditioned medium from resting, PHA or LPS-activated peripheral blood mononuclear cells (PBMC). Medium with LPS or PHA at the same concentration as that used to stimulate the PBMC was used as an additional control. Lysates were subjected to western blotting for activated forms of the mitogen-activated protein kinases (MAPK), Stat1, and Stat3. Western blotting showed phosphorylation of the Jun kinase (JNK), p38, and Erk1/Erk2 MAPK in trophoblasts incubated with conditioned medium from LPS or PHA-activated PBMC but not from medium from resting PBMC, or with PHA or LPS alone. Phosphorylation could be detected as early as 5 min and was still observable by 10 min, the latest time point tested. Similarly, Stat1 and Stat3 phosphorylation was observed within 10 min of exposure to conditioned medium and was still observable 10 min after exposure. Immunohistochemistry also demonstrated nuclear translocation of both Stat1 and Stat3 after stimulation of trophoblasts with medium from activated PBMC. These findings are compatible with the hypothesis that immunologic balance at the maternal-fetal interface is maintained by ongoing "cross-talk" between the fetus (and fetally-derived tissues) and the maternal immune system. Infection of the maternal vaginal tract may disrupt this delicate immunologic balance, initiating inflammatory events that ultimately result in preterm labor.
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PMID:Soluble factors from LPS- and PHA-activated PBMC induce MAPK, Stat1 and Stat3 phosphorylation in primary cultures of human term placental trophoblasts: implications for infection and prematurity. 1690 41


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