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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine CXCL8 is a powerful inducer of directional cell motility, primarily during inflammation. In this study, we found that CXCL8 stimulation led to paxillin phosphorylation in normal neutrophils, and that both CXCL8 receptors (CXCR1 and CXCR2) mediated CXCL8-induced paxillin phosphorylation. In CXCR2-transfected cells, the process depended on G(alphai) and G(alphas) coupling to CXCR2. Dominant negative (DN) paxillin increased CXCL8-induced adhesion and migration, indicating that endogenous paxillin keeps migration at submaximal levels. Furthermore, using activating antibodies to beta1 integrins, analyses with focal adhesion kinase (FAK) DN variant (FRNK) and co-immunoprecipitations of FAK and paxillin, we found that beta1 integrin ligation cooperates with CXCL8-induced stimulation, leading to FAK activation and thereafter to FAK-mediated paxillin phosphorylation. Our findings indicate that paxillin keeps directional motility at a restrained magnitude, and suggest that perturbations in its activation may lead to chemotactic imbalance and to pathological conditions associated with excessive or reduced leukocyte migration.
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PMID:Cell migration to the chemokine CXCL8: paxillin is activated and regulates adhesion and cell motility. 1915 25

IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, and atherosclerosis. We investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would up-regulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT, HEK293 cells, chondrocytes, monocytes, and glioblastoma cells. Inhibition of hypoxia-inducible factor 1alpha inhibited CoCl(2)-induced IL-20 expression. We identified two putative hypoxia response elements in the human il20 gene promoter. Promoter activity assays showed that CoCl(2) mimicked hypoxia-activated luciferase reporter gene expression. In vivo, experimental ischemic stroke up-regulated IL-20 in the sera and brain tissue of rats. IL-20 stained positively in glia-like cells in peri-infarcted lesions, but not in contralateral tissue. Administration of IL-20 mAb ameliorated ischemia-induced brain infarction of rats after experimental ischemic stroke. In vitro, RT-PCR analysis showed that glioblastoma cells, GBM8901, expressed IL-20 and its receptor subunits IL-20R1, IL-20R2, and IL-22R1. IL-20 induced cell proliferation in GBM8901 cells by activating the JAK2/STAT3 and ERK1/2 pathways. IL-20 also induced production of IL-1beta, IL-8, and MCP-1 in GBM8901 cells. We conclude that IL-20 was responsive to hypoxia in vitro and in the ischemic stroke model and that up-regulation of IL-20 in the ischemic brain may contribute to brain injury.
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PMID:IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. 1934 80

Induction of proinflammatory mediators by alveolar macrophages exposed to ambient air particulate matter has been suggested to be a key factor in the pathogenesis of inflammatory and allergic diseases in the lungs. However, receptors and mechanisms underlying these responses have not been fully elucidated. In this study, we examined whether TLR2, TLR4, and the key adaptor protein, MyD88, mediate the expression of proinflammatory cytokines and chemokines by mouse peritoneal macrophages exposed to fine and coarse PM. TLR2 deficiency blunted macrophage TNF-alpha and IL-6 expression in response to fine (PM2.5), while not affecting cytokine-inducing ability of coarse NIST Standard Reference Material (SRM 1648) particles. In contrast, TLR4(-/-) macrophages showed inhibited cytokine expression upon stimulation with NIST SRM 1648 but exhibited normal responses to PM2.5. Preincubation with polymyxin B markedly suppressed the capacity of NIST SRM 1648 to elicit TNF-alpha and IL-6, indicating endotoxin as a principal inducer of cytokine responses. Overexpression of TLR2 in TLR2/4-deficient human embryonic kidney 293 cells imparted PM2.5 sensitivity, as judged by IL-8 gene expression, whereas NIST SRM 1648, but not PM2.5 elicited IL-8 expression in 293/TLR4/MD-2 transfectants. Engagement of TLR4 by NIST SRM 1648 induced MyD88-independent expression of the chemokine RANTES, while TLR2-reactive NIST IRM PM2.5 failed to up-regulate this response. Consistent with the shared use of MyD88 by TLR2 and TLR4, cytokine responses of MyD88(-/-) macrophages to both types of air PM were significantly reduced. These data indicate differential utilization of TLR2 and TLR4 but shared use of MyD88 by fine and coarse air pollution particles.
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PMID:Involvement of TLR2 and TLR4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter. 1940 32

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
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PMID:Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. 1960 29

The outer membrane proteins YadA and invasin of Yersinia pseudotuberculosis promote invasion into mammalian cells through beta(1)-integrins and trigger the production of interleukin (IL)-8. FAK, c-Src and the PI3 kinase were previously found to be important for both YadA- and invasin-promoted uptake. Here, we demonstrate that two different downstream effectors of PI3 kinase, Akt and phospholipase Cgamma1 are required for efficient cell invasion. Inhibition of Akt or phospholipase C-gamma (PLC-gamma)1 by pharmaceutical agents as well as reduced expression of the isoforms Akt1 and Akt2, and of PLC-gamma1 by RNA interference decreased entry of YadA- and Inv-expressing bacteria significantly. In addition, we report that the conventional protein kinases C (PKC)alpha and -beta, positioned downstream of PLC-gamma1, are activated upon Inv- or YadA-promoted cell entry. They colocalize with intracellular bacteria and their depletion by siRNA treatment also resulted in a strong reduction of cell entry. In contrast, neither Akt nor PLC-gamma1, and the PKCs are essential for YadA- and Inv-mediated IL-8 synthesis and release. We conclude that YadA and invasin of Y. pseudotuberculosis both trigger similar signal transduction pathways during integrin-mediated phagocytosis into epithelial cells, which lead to the activation of Akt, PLC-gamma1, PKCalpha and -beta downstream of PI3 kinase, separate from the MAPK-dependent pathway that triggers IL-8 production.
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PMID:Cell invasion of Yersinia pseudotuberculosis by invasin and YadA requires protein kinase C, phospholipase C-gamma1 and Akt kinase. 1968 7

Extracellular nucleotides regulate a variety of cellular responses involved in inflammation via the activation of P2 receptors. Here, we show that nucleotides regulate TLR2-induced neutrophil migration both in vivo and in vitro. The nucleotide scavenger apyrase inhibited neutrophil recruitment in murine air pouches injected with the TLR2 agonist Pam(3)CSK(4). In agreement, the supernatants of either human primary monocytes or monocytic cells (THP-1 and U937) treated with Pam(3)CSK(4) recruited significantly fewer neutrophils when the former cells were treated in the presence of apyrase. As demonstrated with inhibitory Ab, these supernatants induced neutrophil migration due to IL-8 secretion. In addition, IL-8 secretion was markedly diminished by the non-selective P2 receptor antagonists reactive blue 2 and suramin, and by a selective P2Y(6) antagonist, MRS2578. Selective antagonists of P2Y(1) (MRS2500) and P2Y(11) (NF157) did not affect IL-8 release. The knockdown of either P2Y(2) or P2Y(6) with specific shRNA diminished IL-8 secretion from Pam(3)CSK(4)-treated THP-1 cells. Altogether, these results show that extracellular nucleotides, via P2Y(2) and P2Y(6) receptors, regulate neutrophil migration by controlling TLR2-induced IL-8 release from human monocytes. In line with our previous work on TLR4, this study further supports the importance of nucleotides in bacterial-induced neutrophil migration.
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PMID:Concomitant activation of P2Y(2) and P2Y(6) receptors on monocytes is required for TLR1/2-induced neutrophil migration by regulating IL-8 secretion. 1973 76

Toll-like receptors (TLRs) are increasingly implicated in the pathogenesis of cancer. The present study describes TLR expression and function in healthy and malignant airway epithelial cells. The squamous cell carcinoma cell line Detroit-562 was compared with the healthy bronchial epithelial cell line NL-20 and primary human nasal epithelial cells (HNECs). TLR2, TLR3 and TLR5 were present in primary head and neck squamous cell carcinomas (HNSCCs). Consistent with this, Detroit-562 expressed TLR2, TLR3 and TLR5, whereas NL-20 expressed mainly TLR3 and HNECs expressed TLR2-5. In Detroit-562, Pam(3)CSK(4), poly(I:C) and flagellin, ligands for TLR2, TLR3 and TLR5, respectively, induced an up-regulation of intercellular adhesion molecule 1 (ICAM-1), an increase in interleukin (IL)-6 and IL-8 secretion and a decrease in cell viability. Additionally, poly(I:C) affected IL-1beta production and the migratory behaviour of Detroit-562. NL-20 responded with a slight increase in IL-8 secretion upon poly(I:C) stimulation. Poly(I:C) induced a small increase in IL-1beta, IL-6 and IL-8 production in HNECs, while Pam(3)CSK(4) increased viability. The TLR signalling was transcription-dependent, but the pathways involved differed among TLRs as well as cells. In Detroit-562, TLR2 and TLR5 activation was mediated via c-jun N-terminal kinase (JNK)-, p38-, phosphatidylinositol 3-kinase (PI3K)- and nuclear factor (NF)-kappaB-related pathways, while TLR3 was dependent on NF-kappaB. In NL-20, TLR3 signalled via p38, and in HNECs, NF-kappaB, JNK and extracellular signal-regulated kinase (ERK) appeared to be involved. We found that TLR agonists induced a robust response in HNSCCs, characterized by generation of inflammation and cell death. A similar response was not seen in normal epithelial cells. Thus, the TLR system should be considered an important target in future antitumour immunotherapy.
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PMID:Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas. 1974 Mar 21

Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI(2)) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI(2) is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-gamma- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-gamma- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-alpha production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-gamma-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-gamma-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-gamma-signaling. We conclude that PGI(2) exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.
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PMID:Prostacyclin inhibits IFN-gamma-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner. 1991 63

Epidemiologic and occupational studies demonstrated that ambient particulate matter (PM) and diesel exhaust particles (DEP) exert deleterious effects on human cardiopulmonary health, including exacerbation of pre-existing lung disease and development of respiratory infections. The effects of ambient PM on lung cell responsiveness are poorly defined. Human alveolar macrophages (AM) were exposed to SRM 1649 (Washington, DC, urban dust; UD), SRM 2975 (forklift diesel exhaust particles; DEP), and fine or coarse ambient PM collected in Chapel Hill, NC, during the late fall (November) and early summer (June) of 2001-2002. AM were subsequently incubated with lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or calcium ionophore A23817 for 6 or 24 h after PM exposure. UD and DEP markedly suppressed O2- release 24 h post-PM exposure. UD exposure significantly inhibited tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 release after exposure to 10 nanog/ml LPS. DEP significantly suppressed only TNF-alpha and IL-6 release. Suppressed cytokine release may also be produced by reduced cellular cytokine production. Data suggested that decreased cytokine release is not produced by the presence of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon. Comparison of TNF-alpha release after LPS, PMA, or A23817 revealed that suppressive effects of UD are LPS dependent, whereas inhibitory effects of DEP may work across multiple mechanistic pathways. November and June Chapel Hill PM exposure stimulated TNF-alpha and IL-8 release before LPS exposure. Fine and coarse November PM exposure markedly suppressed TNF-alpha release 6 h after LPS stimulation, but appeared to exert a stimulatory effect on IL-8 release 24 h after LPS exposure. June fine and coarse PM suppressed IL-8 release after LPS exposure. Data suggest that seasonal influences on PM composition affect AM inflammatory response before and after bacterial exposure. Overall, delayed or inhibited AM immune responses to LPS after PM exposure suggest human exposure to ambient PM may enhance pulmonary susceptibility to respiratory infections.
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PMID:The effects of ambient particulate matter on human alveolar macrophage oxidative and inflammatory responses. 1995 19

IFN-stimulated gene 15 (ISG15), an ubiquitin-like protein, is rapidly induced by IFN-alpha/beta, and ISG15 conjugation is associated with the antiviral immune response. Japanese encephalitis virus (JEV), a mosquito-borne neurotropic flavivirus, causes severe central nervous system diseases. We investigated the potential anti-JEV effect of ISG15 over-expression. ISG15 over-expression in human medulloblastoma cells significantly reduced the JEV-induced cytopathic effect and inhibited JEV replication by reducing the viral titers and genomes (p<0.05, Student's t-test); it also increased activation of the interferon stimulatory response element (ISRE)-luciferase cis-acting reporter in JEV-infected cells (p<0.05, Chi-square test). Furthermore, Western blotting revealed that ISG15 over-expression increased phosphorylation of IRF-3 (Ser396), JAK2 (Tyr1007/1008) and STAT1 (Tyr701 and Ser727) in JEV-infected cells (P<0.05, Chi-square test). Confocal imaging indicated that nucleus translocation of transcription factor STAT1 occurred in ISG15-over-expressing cells but not in vector control cells post-JEV infection. ISG15 over-expression activated the expression of STAT1-dependent genes including IRF-3, IFN-beta, IL-8, PKR and OAS before and post-JEV infection (p=0.063, Student's t-test). The results enabled elucidation of the molecular mechanism of ISG15 over-expression against JEV, which will be useful for developing a novel treatment to combat JEV infection.
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PMID:ISG15 over-expression inhibits replication of the Japanese encephalitis virus in human medulloblastoma cells. 2003 88


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