Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elastin is a major component of the extracellular matrix. Elastin peptides derived from its degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. Considering the multiple biological effects of ELR the elucidation of the complexity of the signaling pathways will help to better modulate it, mainly in pathological situations such as atherosclerosis.
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PMID:[The elastin-laminin receptor]. 1172 28

The cytokine tumour necrosis factor-alpha (TNF) has been implicated in autoimmune diseases and may play an indirect role in activation of pain pathways. In this study we have investigated the possibility that TNF directly activates cultured neonatal rat dorsal root ganglion (DRG) neurones and provides a signalling pathway from cells in the immune system such as macrophages to sensory neurones. Expression of TNF receptor subtypes (TNFR1 and TNFR2) on sensory neurones was identified using immunohistochemistry, fluorescence-activated cell sorting analysis and RT-PCR. Biochemical and immunocytochemical analysis showed that TNF activated p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) but not p42/p44 MAPK. TNF treatment evoked transient Ca2+-dependent inward currents in 70% of DRG neurones. These TNF-evoked currents were significantly attenuated by ryanodine or thapsigargin or by inclusion of BAPTA in the patch pipette solution. Responses were also evoked in subpopulations of cultured DRG neurones by human mutant TNFs that cross-reacted with rat receptors and selectively activated TNFR1 or TNFR2 subtypes. TNF-evoked transient increases in [Ca2+]i were also detected in 34% of fura-2-loaded DRG neurones. The link between TNF receptor activation and Ca2+ release from stores remains to be elucidated. However, responses to TNF were mimicked by sphingolipids, including sphingosine-1-phosphate, which evoked a transient rises in [Ca2+]i in a pertussis toxin-insensitive manner in fura-2-loaded DRG neurones. We conclude that distinct receptors TNFR1 and TNFR2 are expressed on cultured DRG neurones and that they are functionally linked to intracellular Ca2+ mobilisation, a response that may involve sphingolipid signalling.
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PMID:TNF-alpha receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. 1175 Sep 19

Thymosin alpha 1 (Talpha1), a 28-amino acid, acidic thymic peptide, is a promising natural biological response modifier (BRM), which augments and regulates the immune network and is thought to be immunostimulatory also. Recently, we have reported the ability of Talpha1 to activate macrophages to tumoricidal state. In the present investigation, the activation of the p42/44 MAP kinase (MAPK)/c-Jun NH2 terminal kinase (JNK) pathway in response to in vitro treatment with Talpha1 in murine bone marrow-derived macrophages (BMDMs) has been demonstrated. The activation and expression of phospho-p42/44 MAPK was dose as well as time dependent with maximum expression occurring at 5-15 min following stimulation with 100 ng/ml of Talpha1. The expression of phospho-p42/44 MAPK was inhibited by the MAPK inhibitor, PD98059, pertussis toxin (PTX), tyrosine kinase inhibitor-genistein and P13K inhibitor-wortmannin. Talpha1-induced BMDM tumoricidal functions like the production of NO and TNF-alpha, the key mediator molecules of macrophage cytotoxicity, were also inhibited by the MAPK inhibitor, PD98059, in a dose-dependent manner. These observations suggest that p42/44 MAPK activation is one of the essential signaling events triggered by Talpha1 and may be responsible for the in vitro activation of BMDMs.
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PMID:Involvement of mitogen-activated protein kinases in the signal transduction pathway of bone marrow-derived macrophage activation in response to in vitro treatment with thymosin alpha 1. 1178 69

The elevated level of thrombin has been detected in the airway fluids of asthmatic patients and shown to stimulate cell proliferation in tracheal smooth muscle cells (TSMCs). However, the implication of thrombin in the cell proliferation was not completely understood. In this study, thrombin stimulated [3H]thymidine incorporation and p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation in a time- and concentration-dependent manner in TSMCs. Pretreatment of TSMCs with pertussis toxin (PTX) significantly inhibited [3H]thymidine incorporation and phosphorylation of MAPK induced by thrombin. These responses were attenuated by tyrosine kinase inhibitors genistein and herbimycin A, phosphatidyl inositide (PI)-phospholipase C (PLC) inhibitor U73122, protein kinase C inhibitor GF109203X, removal of Ca2+ by addition of BAPTA/AM plus EGTA, PI 3-kinase inhibitors wortmannin and LY294002, and inhibitor of MEK1/2 PD98059. Furthermore, overexpression of dominant negative mutants, H-Ras-15A and Raf-N4, significantly suppressed p42/p44 MAPK activation induced by thrombin and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. These results conclude that the mitogenic effect of thrombin was mediated through the activation of Ras/Raf/MEK/MAPK pathway. Thrombin-mediated MAPK activation was modulated by PI-PLC, Ca2+, PKC, tyrosine kinase, and PI 3-kinase associated with cell proliferation in canine cultured TSMCs.
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PMID:Thrombin-stimulated cell proliferation mediated through activation of Ras/Raf/MEK/MAPK pathway in canine cultured tracheal smooth muscle cells. 1181 55

Bacterial N-formyl peptides such as N-formyl-methionyl-leucyl-phenylalanine (fMLP) are important mediators of monocyte/macrophage recruitment and activation at the sites of inflammation. In the current study, the role of nitric oxide (NO) in the activation of murine peritoneal macrophages to tumoricidal state in response to in vitro fMLP treatment has been investigated. Murine peritoneal macrophages on treatment with fMLP showed a dose- and time-dependent production of NO together with increased tumoricidal activity against P815 mastocytoma cells. L-NMMA, a specific inhibitor of L-arginine pathway, inhibited the fMLP-induced NO secretion and macrophage-mediated tumoricidal activity against P815 cells. These results indicate the L-arginine-dependent production of NO to be one of the effector mechanisms contributing to the tumoricidal activity of fMLP-treated macrophages. The expression of iNOS protein and iNOS mRNA is also observed. The pharmacological inhibitors genistein, wortmannin, H7, PD98059, TPCK, and pertussis toxin (PTX) blocked the fMLP-induced NO production, suggesting the involvement of tyrosine kinases, PI3K, PKC, p42/44 MAPkinase, NF-kappa B, and G-proteins. The expression of phospho-p42/44 MAPK and phospho-I kappa B was also observed. The role of protein phosphatases in the above pathway has been suggested using the specific inhibitors of these phosphatases, i.e., okadaic acid and sodium orthovanadate.
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PMID:fMLP-induced in vitro nitric oxide production and its regulation in murine peritoneal macrophages. 1181 47

The role of Rho proteins in lysophosphatidic acid (LPA)-mediated induction of cyclo-oxygenase-2 (Cox-2) was investigated in renal mesangial cells. Previous studies had shown that toxin B, an inhibitor of Rho, Rac and Cdc42, suppressed Cox-2 induction. A role for RhoA in pertussis toxin-sensitive LPA signalling was excluded with C3 transferase from Clostridium limosum, used as the fusion toxin C2IN-C3 (where C2IN is part of the C2I toxin of C. botulinum). Incubation of the cells with C2IN-C3 disrupted cytosolic actin stress fibres, but had no effect on Cox-2 induction. Similarly, activation of p42/44 mitogen-activated protein kinase (MAP kinase), an upstream step in Cox-2 induction, was inhibited by toxin B, but not affected by C2IN-C3. Upon treatment with toxin B, focal adhesion kinase and paxillin were dephosphorylated at tyrosine residues and the actin cytoskeleton was completely destroyed. An intact cytoskeleton, however, was not required for p42/44 MAP-kinase activation or Cox-2 induction, as shown by the actin-depolymerizing agent cytochalasin D. Toxin B did not influence functionality of LPA receptors, because G(i)-mediated Ca(2+) release from intracellular stores remained unchanged. Within 1 h, toxin B inactivated and translocated RhoA and Cdc42 to the cellular membranes. Within the same time frame, monoglucosylated Rac1 was degraded. Direct stimulation of Rho proteins by cytotoxic necrotizing factor type 1 (CNF1) induced Cox-2 expression, which was sensitive to inhibition of the MAP-kinase pathway by PD98059, but not to an inhibitor of RhoA kinase. By exclusion of RhoA and non-specific cytoskeletal effects, the results in the present study indicate an important role for Rac and/or Cdc42 in pertussis toxin-sensitive LPA-mediated Cox-2 induction.
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PMID:Role of Rac and Cdc42 in lysophosphatidic acid-mediated cyclo-oxygenase-2 gene expression. 1182 37

In some tissues, rapid effects of estrogens have been described at the plasma membrane level including activation of the MAPK activity. In rat adipocytes, the present study demonstrates that physiological concentrations (0.1-10 nM) of E2 rapidly activate the p42/p44 MAPK. This effect was blocked by the pure estrogen antagonist, ICI 182 780, and appeared specific for E2 because 17alpha-E2, T, and progesterone failed to change the MAPK activity. Pertussis toxin; PP2, a selective inhibitor of Src family kinase; and wortmannin all reduced the magnitude of MAPK activation by E2 suggesting involvement of the Gi-protein/Src family kinase/PI3K pathway. Classical PKCs and MAPK kinase were also involved in MAPK activation by E2. Interestingly, this activation was observed in late but not early differentiated rat preadipocytes, and the immunoreactive ER(alpha) protein was detected only in adipocyte membrane, suggesting that the adipocyte membrane structure is required for the nongenomic effect of E2. Moreover, E2 induced a rapid nuclear translocation of MAPK together with a fast MAPK- dependent activation of cAMP response element binding protein leading to a transcriptional activation of cAMP response element binding protein-responsive genes and reported plasmids. However, the E2 increase in adipocyte activator protein-1 DNA binding does not seem to be fully explained by the E2 activation of the MAPK pathway. This study provides clear evidence for an additional nongenomic mechanism whereby estrogens may exert their control on adipose tissue metabolism.
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PMID:Rapid nongenomic E2 effects on p42/p44 MAPK, activator protein-1, and cAMP response element binding protein in rat white adipocytes. 1186 15

1. Previous studies have shown that the histamine H(1) receptor activates p42/p44 mitogen-activated protein kinases (MAPK) in DDT(1)MF-2 smooth muscle cells via a phosphatidylinositol 3-kinase (PI-3K)-dependent pathway. In this study the effect of histamine H(1) receptor stimulation on protein kinase B (PKB) and p70 S6 kinase, both of which are downstream targets of PI-3K, has been investigated. Increases in PKB and p70 S6 kinase activation were monitored by Western blotting using phospho-specific PKB (Ser(473)) and p70 S6 kinase (Thr(421)/Ser(424)) antibodies. 2. Histamine stimulated time and concentration-dependent increases in the phosphorylation of PKB and p70 S6 kinase in DDT(1)MF-2 cells. Both responses were completely inhibited by the histamine H(1) receptor antagonist mepyramine and following pre-treatment with pertussis toxin, to block G(i)/G(o) protein dependent pathways. 3. The PI-3K inhibitors wortmannin (IC(50) 5.9+/-0.5 nM) and LY 294002 (IC(50) 6.9+/-0.8 microM) attenuated the increase in PKB phosphorylation induced by histamine (100 microM) in a concentration-dependent manner. 4. Histamine-induced increases in p70 S6 kinase phosphorylation were partially sensitive to rapamycin (20 nM; 68% inhibition) but completely blocked by wortmannin (100 nM), LY 294002 (30 microM) and the MAPK kinase inhibitor PD 98059 (50 microM). 5. In summary, these data demonstrate that the histamine H(1) receptor stimulates PKB and p70 S6 kinase phosphorylation in DDT(1)MF-2 smooth muscle cells. However, functional studies revealed that histamine does not stimulate DDT(1)MF-2 cell proliferation or attenuate staurosporine-induced caspase-3 activity. The challenge for future research will be to link the stimulation of these kinase pathways with the physiological and pathophysiological roles of the histamine H(1) receptor.
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PMID:Stimulation of protein kinase B and p70 S6 kinase by the histamine H1 receptor in DDT1MF-2 smooth muscle cells. 1195

Exocytosis in mast cells, effector cells of allergic and inflammatory reactions, can be activated, in a receptor-independent manner, by a family of polycationic molecules (e.g. the Basic Secretagogues of mast cells) that activate directly heterotrimeric G-proteins that control exocytosis. We have recently shown that pertussis toxin (Ptx)-sensitive Gi-protein(s), activated directly by Basic Secretagogues, also stimulate protein tyrosine phosphorylation and activation of the p42/p44 MAP kinases, via a mechanism that involves protein kinase C (PKC), phosphatidylinositol-3-kinase and Ca2+ as intermediates (J. Pharmacol. Exp. Ther. 289 (1999) 1654). In this paper, we have investigated the role of endocytosis in this receptor-independent, G-protein-mediated signaling. Using mechanistically distinct inhibitors of clathrin-mediated endocytosis, we demonstrate that protein tyrosine phosphorylation and activation of p42/p44 MAP kinases are endocytosis-dependent. In contrast, Gi-stimulated exocytosis is unaffected. We show further that Gi activation results in recruitment of clathrin from the cytosol to the plasma membrane. Taken together, our results indicate that signal transduction between G-proteins and the components of the MAP kinase activation cascade is dependent on clathrin-mediated endocytosis and can occur independently of a 7 TM cell surface receptor.
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PMID:Gi-mediated activation of the p42/p44 mitogen-activated protein kinases by receptor mimetic basic secretagogues is abrogated by inhibitors of endocytosis. 1201 9

The role of monocyte chemoattractant protein-1 (MCP-1) in mediating the infiltration and activation of monocytes/macrophages into the sites of inflammation or tumor growth is well documented, but the molecular mechanism(s) involved in the process is poorly understood. In the current investigation, we demonstrate activation of the p42/44 MAPK-mediated signal transduction in murine peritoneal macrophages on stimulation with MCP-1 (10-100 ng/ml) in vitro. The p42/44 MAPK activation was determined by studying the expression of the phosphorylated p42/44 MAPK (Thr202/Tyr204) in the MCP-1-treated macrophages. This response was found to be rapid and time dependent, detectable within 5 min of MCP-1 stimulation. PD98058 (5-50 microM), a specific inhibitor of MAPK kinase (MEK) inhibited the p42/44 MAPK phosphorylation, indicating the specificity of the response. Furthermore, the MCP-1-induced phosphorylation of p42/44 MAPK was found to be blocked by pertussis toxin (100 ng/ml), tyrosine kinase inhibitor-genestein (10 ng/ml), PI3K inhibitor-wortmannin (20-200 microM), and anti-CCR2 antibody (2.5 microg/ml). Additionally, phosphorylation of JNK and activation of the transcription factor, c-Jun, were also noted in response to MCP-1 treatment. Lastly, the MCP1-induced p42/44 MAPK activity was correlated with the functional activation of macrophages by demonstrating the dose-specific inhibition of actin polymerization, macrophage-mediated tumor cell cytotoxicity, and tumor necrosis factor-alpha (TNF-alpha) transcription/production afforded by PD98059 in the MCP-1-treated macrophages. Taken together, these data suggest the involvement of the p42/44 MAPK/c-Jun pathway in the signal transduction process, leading to activation of murine peritoneal macrophages.
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PMID:Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation. 1206 Apr 90


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