Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus (HIV)-Tat plays an important role in virus replication and in various aspects of host immune responses, including dysregulation of cytokine production. IL-10, an anti-inflammatory cytokine, is up-regulated during the course of HIV infection representing an important pathway by which HIV may induce immunodeficiency. Here we show that extracellular as well as intracellular Tat induced IL-10 expression in normal human monocytes and promonocytic THP-1 cells. The signaling pathways involved in the regulation of IL-10 production by endogenous Tat remain unknown. To understand the molecular mechanism underlying intracellular Tat-induced IL-10 transcription, we employed a retroviral expression system to investigate the role of MAPKs and the transcription factor(s) involved. Our results suggest that an inhibitor specific for the ERK1/2, PD98059, selectively blocked intracellular Tat-induced IL-10 expression in THP-1 cells. Furthermore, intracellular Tat activated the CREB-1 transcription factor through Ser(133) phosphorylation that was regulated by ERK MAPK as determined by IL-10 promoter analysis and gel shift assays. Overall, our results suggest that intracellular HIV-Tat induces IL-10 transcription by ERK MAPK-dependent CREB-1 transcription factor activation through Ser(133) phosphorylation.
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PMID:Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells. 1692 Jul 14

Besides their microbicidal functions, human beta-defensins (hBD) and LL-37 activate different immune and inflammatory cells, and their expression is enhanced in inflamed skin and cutaneous wound sites. To protect against pathogens, the skin produces antimicrobial peptides including hBDs and LL-37. Therefore, the aim of our study was to investigate whether hBDs participate in cutaneous inflammation and wound healing by inducing keratinocyte migration, proliferation, and production of proinflammatory cytokines/chemokines. We found that hBD-2, -3, and -4 but not hBD-1 stimulated human keratinocytes to increase their gene expression and protein production of IL-6, IL-10, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-3alpha, and RANTES. This stimulatory effect was markedly suppressed by pertussis toxin and U-73122, inhibitors for G protein and phospholipase C, respectively. We also demonstrated that hBDs elicited intracellular Ca2+ mobilization, and increased keratinocyte migration, and proliferation. In addition, these peptides induced phosphorylation of EGFR, signal transducer and activator of transcription (STAT)1, and STAT3, which are intracellular signaling molecules involved in keratinocyte migration and proliferation. In our study, inhibition of these molecules significantly reduced hBD-mediated keratinocyte migration and proliferation. In conclusion, this study provides evidence that human antimicrobial peptides may be involved in skin immunity through stimulating cytokine/chemokine production, and participate in wound healing by promoting keratinocyte migration and proliferation.
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PMID:Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. 1729 32

Loss of tolerance to self-Ags in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease, is associated with dysregulation of T cell signaling, including the depletion of total levels of lymphocyte-specific protein kinase (Lck) from sphingolipid-cholesterol-enriched membrane microdomains (lipid rafts). Inhibitors of 3-hyroxy-3-methylgluteryl CoA reductase (statins) can modify the composition of lipid rafts, resulting in alteration of T cell signaling. In this study, we show that atorvastatin targets the distribution of signaling molecules in T cells from SLE patients, by disrupting the colocalization of total Lck and CD45 within lipid rafts, leading to a reduction in the active form of Lck. Upon T cell activation using anti-CD3/anti-CD28 in vitro, the rapid recruitment of total Lck to the immunological synapse was inhibited by atorvastatin, whereas ERK phosphorylation, which is decreased in SLE T cells, was reconstituted. Furthermore, atorvastatin reduced the production of IL-10 and IL-6 by T cells, implicated in the pathogenesis of SLE. Thus, atorvastatin reversed many of the signaling defects characteristic of SLE T cells. These findings demonstrate the potential for atorvastatin to target lipid raft-associated signaling abnormalities in autoreactive T cells and provide a rationale for its use in therapy of autoimmune disease.
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PMID:Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. 1708 61

The overactivation of macrophages causes abnormal cell death and chronic inflammatory diseases. Therefore, the modulation of macrophage-mediated cytotoxicity is expected to become a new therapeutic strategy for various inflammatory diseases. In this study, three types of short chain fatty acids (sodium butyrate (NaB), sodium phenylbutyrate (NaPB), sodium phenylacetate (NaPA)) were found to have anti-inflammatory effects in IFN-gamma-stimulated RAW 264.7 cells. They inhibited the expression of iNOS, TNF-alpha, and IL-6 induced by IFN-gamma, while they enhanced the expression of the anti-inflammatory cytokine, IL-10. Their potency as anti-inflammatory agents was in the order of NaB>NaPB>NaPA. Further mechanistic studies revealed these three agents to repress the DNA binding and transcriptional activities of NF-kappaB, which is an important modulator of inflammation. In addition, these agents repressed the IFN-gamma-induced ERK1/2 phosphorylation without affecting the Jak/STAT activities. The potency of NF-kappaB and ERK inhibition was also in the order of NaB>NaPB>NaPA. The results suggest that the NF-kappaB and ERK signaling pathways are at least in part involved in the anti-inflammatory activities of these SCFAs. Considering that SCFAs are normally present in the body and have few side effects, they might be promising agents for the prevention and/or treatment of various inflammatory diseases.
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PMID:Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: involvement of NF-kappaB and ERK signaling pathways. 1716 19

IL-10 is a critical cytokine in determining host susceptibility to Leishmania spp. We previously demonstrated that macrophage-derived IL-10 could contribute to disease exacerbation, but the mechanisms whereby Leishmania infections led to IL-10 induction were not fully understood. In this study, we demonstrated that infection of macrophages with Leishmania amazonensis amastigotes led to the activation of the MAPK, ERK1/2. This activation was required, but not sufficient for IL-10 induction. In addition to ERK activation, an inflammatory stimulus, such as low m.w. hyaluronic acid from the extracellular matrix, must also be present. The combination of these two signals resulted in the superinduction of IL-10. We also demonstrated that IgG on the surface of Leishmania amastigotes was required to achieve maximal IL-10 production from infected macrophages. Surface IgG engages macrophage FcgammaR to induce ERK activation. Macrophages lacking FcgammaR, or macrophages treated with an inhibitor of spleen tyrosine kinase, the tyrosine kinase that signals via FcgammaR, failed to activate ERK and consequently failed to produce IL-10 following infection with Leishmania amastigotes. We confirmed that ERK1/2 activation led to the phosphorylation of histone H3 at the IL-10 promoter, and this phosphorylation allowed for the binding of the transcription factor, Sp1, to the IL-10 promoter. Finally, the administration of U0126, an inhibitor of ERK activation, to infected mice resulted in decreased lesion progression with reduced numbers of parasites in them. Thus, our findings reveal an important role of MAPK, ERK signaling in the pathogenesis of Leishmania infection.
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PMID:Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. 1720 71

The aim of the present study is to probe the anti-inflammatory potential of the plant Boswellia serrata by studying the effect of the crude extract and the pure compound isolated from it on key inflammatory mediators like TNFalpha, IL-1beta, and NO thus enabling the understanding of the key signaling events involved. The crude methanolic extract and the pure compound were analysed for their inhibitory effect on TNFalpha, IL-1beta and IL-6. The results demonstrated that all three cytokines are down regulated when PBMCs are cultured in the presence of crude extract or the pure compound at various time points. Observations on Th1/Th2 cytokines revealed marked down regulation of Th1 cytokines IFNgamma and IL-12 while the Th2 cytokines IL-4 and IL-10 were up regulated upon treatment with crude extract and pure compound. The extract and the pure compound isolated also showed considerable inhibition of NO production in activated RAW 264.7 cells, possibly via suppression of inducible NO synthase mRNA expression. Further to elucidate the underlying mechanism of action the effect of 12-ursene 2-diketone on LPS-induced activation of MAPK has also been examined. Our results demonstrated that 12-ursene 2-diketone inhibits the expression of pro-inflammatory cytokines and mediators via inhibition of phosphorylation of the MAP kinases JNK and p38 while no inhibition was seen in ERK phosphorylation in LPS-stimulated PBMCs. The above study therefore indicates that the crude methanolic extract and the isolated pure compound are capable of carrying out a natural anti-inflammatory activity at sites where chronic inflammation is present by switching off the pro-inflammatory cytokines and mediators, which initiate the process.
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PMID:Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFalpha, IL-1beta, NO and MAP kinases. 1732 70

Trauma-hemorrhage produces immunodepression in males but not in proestrus females and this difference is due to the presence of high estrogen in proestrus females. Although skin is the largest immunological organ of the body and is considered the first line of defense, no study to-date has examined whether trauma-hemorrhage has any effects on keratinocytes which are the major epidermal cell type (>90%) of skin. We therefore examined whether epidermal keratinocytes inflammatory response and the signal transduction pathways involved in the inflammatory response are altered following trauma-hemorrhage. C3H/HeN mice were subjected to trauma-hemorrhage and 2h thereafter; keratinocytes were harvested and stimulated with LPS for 24h (5 microg/ml). Inflammatory mediators, Toll-like receptor (TLR) and myeloid differentiation adaptor protein (MyD88) expression, and the activation of mitogen-activated protein kinase (MAPK) were determined. Trauma-hemorrhage increased the production of IL-6, IL-10, IL-12 and TNF-alpha enhanced the expression of TLR4, MyD88 as well as the activation of MAPK proteins (p38, ERK and JNK) in epidermal keratinocytes. However, administration of a single dose of 17beta-estradiol following trauma-hemorrhage prevented the increase in these inflammatory parameters under those conditions. These findings suggest that 17beta-estradiol normalizes epidermal keratinocytes inflammatory responses following trauma-hemorrhage by preventing the upregulation of TLR4-mediated MAPK activation.
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PMID:17 Beta-estradiol normalizes Toll receptor 4, mitogen activated protein kinases and inflammatory response in epidermal keratinocytes following trauma-hemorrhage. 1740 39

MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1(-/-) macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1(-/-) macrophages produced more proinflammatory cytokines such as TNF-alpha and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-alpha, IL-6, IL-10, and MIP-1alpha, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.
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PMID:Knockout of Mkp-1 enhances the host inflammatory responses to gram-positive bacteria. 1740 16

Macrophages acquire their capacity for efficient phagocytosis of apoptotic cells during their differentiation from monocytes. The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly up-regulated during this maturation program. We report that addition of PPARgamma antagonist during differentiation of human monocytes to macrophages significantly reduced the capacity of macrophages to engulf apoptotic neutrophils, but did not influence phagocytosis of opsonized bacteria. Macrophage-specific deletion of PPARgamma in mice also resulted in decreased uptake of apoptotic cells. The antagonist acted in a dose-dependent manner during the differentiation of human macrophages and could also reverse the previously observed augmentation of phagocytosis by glucocorticoids. Blocking activation of PPARgamma led to down-regulation of molecular elements (CD36, AXL, TG2 and PTX3) of the engulfment process. Inhibition of PPARgamma-dependent gene expression did not block the anti-inflammatory effect of apoptotic neutrophils or synthetic glucocorticoid, but significantly decreased production of IL-10 induced by LPS. Our results suggest that during differentiation of macrophages natural ligands of PPARgamma are formed, regulating the expression of genes responsible for effective clearance of apoptotic cells and macrophage-mediated inflammatory responses.
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PMID:PPARgamma-dependent regulation of human macrophages in phagocytosis of apoptotic cells. 1740 94

We have presently studied the in vitro, ex vivo and in vivo immunopharmacological effects of VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid]. This compound reduced the secretion of IL-1beta, TNF-alpha and IL-10 from purified murine macrophages stimulated "in vitro" with lipopolysaccharide (LPS), and it also modified the signaling pathways induced in these cells by LPS entailing reduced activation of NF-kappaB and p38 MAP kinase pathways along with up-regulation of ERK pathways. VGX-1027 appeared to spare T cell function as it was unable to modify the proliferation and/or secretion of IL-2, IFN-gamma and IL-4 induced in purified murine CD4+ T cells from stimulation with either CD3+CD28 or ConA. These effects on macrophages may account for the capacity of VGX-1027 to markedly ameliorate the course of both acute and chronic immunoinflammatory diseases in mice such as carrageenan-induced pleurisy, LPS-induced lethality and type II collagen-induced arthritis. Acute and subacute toxicological studies show that the drug is not toxic at the doses that exert biological effects in these preclinical models. These data warrant additional studies for the potential use of VGX-1027 in the clinical setting.
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PMID:In vitro, ex vivo and in vivo immunopharmacological activities of the isoxazoline compound VGX-1027: modulation of cytokine synthesis and prevention of both organ-specific and systemic autoimmune diseases in murine models. 1744 26


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