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

Mechanisms of neutrophil activation in response to chemoattractants remain incompletely understood. We have recently reported a Ras-mediated c-Raf pathway leading to the activation of mitogen-activated protein (MAP) kinase in human neutrophils stimulated with the chemoattractant formyl-Met-Leu-Phe (FMLP). However, concern that Raf activation may not fully account for the early FMLP-mediated human neutrophil responses prompted us to investigate the activation of MAP kinase/ERK kinase (MEK) by MEK kinase (MEKK). In cell lysates we identified protein species at 180, 160, 110, 72, and 54 kDa with a monoclonal antibody to MEKK. Activation of MEKK was determined on immunoprecipitates from FMLP-stimulated neutrophils by in vitro kinase assay, which utilized both MEK1 and MEK2 as substrates. It was rapid, detectable at 30 s and reaching a plateau at 5 min, and it was inhibited in a dose-dependent fashion by a specific phosphatidylinositol 3-kinase inhibitor, wortmannin. Partial inhibition by pertussis toxin was observed. We were unable to show inhibition of the MEKK response by GF 109203X, a protein kinase C-specific inhibitor. These data indicate that in neutrophils activation of MEKK in addition to Raf may underlie stimulation of MAP kinase and other MAP kinase homologues by FMLP.
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PMID:Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation. 896 28

Neutrophils play a major role in the host defence by producing reactive oxygen species. These products are liberated by activated cells and are known to cause endothelial cell injury and damage. The present study shows that low-density lipoproteins increase superoxide anion production by twofold in polymorphonuclear leukocytes stimulated by formyl-Met-Leu-Phe in vitro. Moreover, LDL induced a large increase in phosphoinositides and cytosolic-free calcium. Data from experiments performed on neutrophils treated with pertussis toxin, staurosporine, propranolol or niflumic acid suggest that modulation of phospholipase D and A2 activities could be involved in the modification by LDL of leukocyte response to formyl-Met-Leu-Phe. LDL lipid moiety could play a key role in their action on polymorphonuclear functions because cholesterol was exchanged between lipoproteins and cells that can modify membrane fluidity and interact with the formyl-Met-Leu-Phe receptor.
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PMID:Effects of human low-density lipoproteins on superoxide production by formyl-methionyl-leucyl-phenylalanine activated polymorphonuclear leukocytes. 905 46

We studied the chemotactic effects of calcitonin gene-related peptide, vasoactive intestinal peptide, substance P (SP), and secretoneurin on PBMC and PBL using micropore filter assays. All four peptides induced migration of PBMC, whereas only calcitonin gene-related peptide, vasoactive intestinal peptide, and SP were chemotactic for PBL. Secretoneurin, known to induce monocyte chemotaxis, was unable to affect lymphocyte migration. Effects of SP on PBL were characterized by checkerboard analyses and represented true chemotaxis. Both T and B cells responded chemotactically to SP, the functional activity of SP residing in its C-terminal amino acid sequence. Involvement of neurokinin (NK) receptors was supported by inhibition of SP-induced migration of PBL with an NK1 receptor antagonist and induction of migration with [Sar9, Met(O2)11]SP and [PyrGlu6, Pro9]SP(6-11), two specific agonists for NK1 receptors, but not with [beta-Ala8]NK A(4-10), an agonist for NK2 receptors. PBL chemotaxis to SP was abolished by inhibition of tyrosin kinase but not by that of protein kinase C. Preincubation of PBL with pertussis or cholera toxin inhibited SP chemotaxis, indicating that in PBL, NK receptors for chemotaxis probably are coupled with G protein and involve a tyrosin kinase signaling pathway. We conclude that, together with calcitonin gene-related peptide and vasoactive intestinal peptide, SP is a lymphocyte chemoattractant, whereas secretoneurin, which is coreleased from sensory nerve endings, is not.
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PMID:Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. 910 59

CD38 is a type II transmembrane glycoprotein possessing an NAD+ glycohydrolase activity in its extracellular domain. We previously reported that the ligation of CD38 by a monoclonal antibody (mAb), HB-7, induces the tyrosine phosphorylation of cellular proteins including p120(c-cbl) in differentiated human myeloid cell lines and that the phosphorylated p120(c-cbl) is capable of binding to phosphatidylinositol (PI) 3-kinase. In the present study, we found that the agonistic anti-CD38 mAb markedly potentiates superoxide generation stimulated by chemotactic formyl-Met-Leu-Phe receptors in the CD38-producing cells. HB-7 neither generated superoxide by itself nor enhanced the cell response induced by phorbol 12-myristate acetate, indicating that the potentiating action of the anti-CD38 mAb is specific for the stimulation by the GTP-binding protein (G1)-coupled membrane receptors. The potentiation by HB-7 was abolished by prior treatment of the cells with a tyrosine kinase inhibitor, pertussis toxin, or a potent PI 3-kinase inhibitor, wortmannin. HB-7 also enhanced the product formation of PI 3-kinase in response to the chemotactic receptor stimulation, without significant changes in the receptor-stimulated accumulations of inositol-1,4,5-trisphosphate, arachidonate release, and intracellular Ca2+. These results indicate that the CD38-induced tyrosine phosphorylation has a cross-talk with the chemotactic receptor/G1-mediated signal transduction pathway resulting in the enhancement of superoxide generation, probably through the activation of PI 3-kinase.
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PMID:Potentiation of chemotactic peptide-induced superoxide generation by CD38 ligation in human myeloid cell lines. 919 38

Neutrophils produce superoxide anion (O2-) when exposed in vitro to Aroclor 1242, a mixture of polychlorinated biphenyls (PCBs). The mechanism for this effect shares some similarities with the mechanism by which the physiologic agonist f-Met-Leu-Phe (fMLP) activates neutrophils. Since production of O2- in response to fMLP involves GTP-binding proteins and protein tyrosine kinases (PTKs), the current study was undertaken to determine whether these signalling pathways are involved in PCB-induced neutrophil activation. Neutrophils exposed to Aroclor 1242 or fMLP produced significant O2-. Pretreatment of intact neutrophils with pertussis toxin or cholera toxin or exposure of permeabilized cells to GDPbetaS significantly inhibited O2- production in fMLP-treated neutrophils but did not alter the response to Aroclor 1242. Pretreatment with genistein, an inhibitor of PTKs, significantly inhibited O2- production in both Aroclor 1242- and fMLP-treated neutrophils; however, daidzein, a structural analogue of genistein which lacks activity against PTKs, was without effect. Exposure of neutrophils to Aroclor 1242 resulted in an increase within 1 min in tyrosine phosphorylation of proteins in the 40 and 60 kDa molecular mass ranges which persisted for up to 10 min. Similar results were obtained with 2,2',4,4'-tetrachlorobiphenyl (2,2',4,4'-TCB), a PCB congener that stimulates O2- production. In contrast, 3,3',4,4',5-pentachlorobiphenyl (3,3',4,4',5-PeCB), a congener that does not generate O2-, caused only a transient increase in tyrosine phosphorylation of proteins in the 40 kDa range with no effect on 60 kDa proteins. These data suggest that Aroclor 1242 activates neutrophils to produce O2- by a mechanism that requires tyrosine kinase activity; however, heterotrimeric G-proteins are not likely to be involved.
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PMID:Protein tyrosine kinase involvement in the production of superoxide anion by neutrophils exposed to Aroclor 1242, a mixture of polychlorinated biphenyls. 925 58

Application of either acetylcholine (ACh), dopamine (DA), histamine (HA), or Phe-Met-Arg-Phe-NH2 (FMRFamide) induces a K+-current response in the identified neurons of Aplysia under voltage clamp. This type of response is mediated by a pertussis toxin (PTX)-sensitive G-protein, Gi or Go. Extracellular application of 60 microM phorbol dibutyrate (PDBu), an activator of protein kinase C (PKC), to these cells markedly depressed all the K+-current responses to ACh, DA, HA, and FMRFamide. The depressing effect of PDBu lasted for at least 60 min despite continuous washing with the normal perfusing medium. Application of PKC inhibitors such as 100 microM H-7 or 10 microM staurosporine and PKCI(19-31) prior to the application of PDBu significantly decreased the depressing effects of PDBu. In contrast, an intracellular injection of okadaic acid (OA), an inhibitor of protein phosphatase 1 and 2A, significantly augmented the blocking effect of PDBu. Intracellular injection of the PKC catalytic subunit induced a similar depressing effect as observed with PDBu. The dose-response curves obtained with different transmitters all shifted downward after the activation of PKC, but the ED50 of each transmitter remained unchanged. Furthermore, the K+-current responses induced by the intracellular application of GTPgammaS were not depressed at all, even after the receptor-induced K+-current responses of the same cell were markedly depressed. These results strongly suggest that PKC phosphorylated a certain coupling site between the receptor and G-protein, and impaired the signal transduction necessary for triggering the K+-channel opening.
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PMID:Functional uncoupling between the receptor and G-protein as the result of PKC activation, observed in Aplysia neurons. 927 Nov 55

The monomeric G-protein Ras is now considered to function as an initial regulator of multiple signaling pathways in both normal and transformed cell types. Adhesion and chemoattractant receptors are known to trigger activation of Ras in human neutrophils, but the signaling mechanism that activates Ras has only been partially elucidated. The present results show that in neutrophils, a time- and dose-dependent f-Met-Leu-Phe (FMLP)-induced activation of Ras is mediated by Gi2-proteins, because such activation is inhibited by pertussis toxin and because direct stimulation of heterotrimeric G-proteins with AlF4- is sufficient to activate Ras. Pretreatment of neutrophils with tyrosine kinase inhibitors, i.e. genistein or erbstatin that completely block FMLP-stimulated protein tyrosine phosphorylations, did not affect the FMLP-induced activation of Ras. Moreover, FMLP did not induce any detectable translocation of Grb2 and Sos to the plasma membrane of neutrophils. Other signaling molecules, such as protein kinase C, phosphatidylinositol 3-kinase and Ca2+, do not appear to be involved in the FMLP-induced Ras activation. Instead, stimulation of neutrophils with FMLP or C5a, the latter of which also activates Gi2-proteins, resulted in transient inhibition of the activity of Ras GTPase-activating proteins (GAP) with kinetics that correlated well with the kinetics of Ras activation. Moreover, decreased Ras-GAP activity was found in p120-GAP but not in neurofibromin immunoprecipitates of FMLP-stimulated cells. These results suggest that tyrosine kinase-dependent Ras exchange factors do not contribute to the FMLP-induced activation of Ras but that such activation is mediated via inhibition of p120-GAP in neutrophils.
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PMID:Chemotactic peptide-induced activation of Ras in human neutrophils is associated with inhibition of p120-GAP activity. 928 61

The signal transduction of the formyl-Met-Leu-Phe (FMLP) receptor in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes mellitus (NIDDM) was compared to that of PMNLs obtained from healthy volunteers. According to our previous studies in this group of patients neither the decrease in insulin binding capacity nor the enhanced insulin-degrading enzyme activity was involved. In control PMNLs, 10 nM FMLP induced a pertussis toxin-sensitive increase in phosphatidyl inositol (PI) cleavage and a subsequent Ca2+ signaling from the intracellular pools. On the other hand, the FMLP-induced protein kinase C (PKC) activation and translocation into the membrane could not be detected in these cells via the measurement of 32P incorporation into histone. In contrast, in PMNLs of this special group of patients suffering from NIDDM the FMLP stimulus produced a significantly low increase in PI cleavage and Ca2+ signaling from the intracellular pools. Moreover, in resting PMNLs of these patients with NIDDM, not only the [Ca2+]i but also the membrane-bound PKC activity was found to be significantly increased. In addition, PKC translocation into the cell membrane of diabetic PMNLs could be further triggered with FMLP as judged by the measurement of 32P incorporation into histone. Based on these results, it appears that the signaling of FMLP receptors in PMNLs of some NIDDM patients may have an alternative pathway through Ca2+ influx from extracellular medium, arachidonic acid cascade, and PKC activation.
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PMID:Altered postreceptor signal transduction of formyl-Met-Leu-Phe receptors in polymorphonuclear leukocytes of patients with non-insulin-dependent diabetes mellitus. 943 1

Formylated peptides (e.g. n-formyl-Met-Leu-Phe (fMLP)) and platelet-activating factor (PAF) mediate chemotactic and cytotoxic responses in leukocytes through receptors coupled to G proteins that activate phospholipase C (PLC). In RBL-2H3 cells, fMLP utilizes a pertussis toxin (ptx)-sensitive G protein to activate PLC, whereas PAF utilizes a ptx-insensitive G protein. Here we demonstrate that fMLP, but not PAF, enhanced intracellular cAMP levels via a ptx-sensitive mechanism. Protein kinase A (PKA) inhibition by H-89 enhanced inositol phosphate formation stimulated by fMLP but not PAF. Furthermore, a membrane-permeable cAMP analog 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) inhibited phosphoinositide hydrolysis and secretion stimulated by fMLP but not PAF. Both cpt-cAMP and fMLP stimulated PLCbeta3 phosphorylation in intact RBL cells. The purified catalytic subunit of PKA phosphorylated PLCbeta3 immunoprecipitated from RBL cell lysate. Pretreatment of intact cells with cpt-cAMP and fMLP, but not PAF, resulted in an inhibition of subsequent PLCbeta3 phosphorylation by PKA in vitro. These data demonstrate that fMLP receptor, which couples to a ptx-sensitive G protein, activates both PLC and cAMP production. The resulting PKA activation phosphorylates PLCbeta3 and appears to block the ability of Gbetagamma to activate PLC. Thus, both fMLP and PAF generate stimulatory signals for PLCbeta3, but only fMLP produces a PKA-dependent inhibitory signal. This suggests a novel mechanism for the bidirectional regulation of receptors which activate PLC by ptx-sensitive G proteins.
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PMID:Differential regulation of formyl peptide and platelet-activating factor receptors. Role of phospholipase Cbeta3 phosphorylation by protein kinase A. 955 82

This study was designed to characterize platelet-activating factor receptor (PAF-R) expression and function in normal and cancerous human colonic epithelial cells. PAF-R gene transcripts were analyzed by reverse transcription-polymerase chain reaction and Southern blot, using three sets of primers corresponding either to the coding region of the human PAF-R sequence (polymerase chain reaction product: 682 base pairs (bp)) or to the leukocyte- and tissue-type transcripts of 166 and 252 bp, respectively. An elongated splice variant was identified in the 5'-untranslated region of the tissue-type PAF-R transcript (334 bp) in colonic epithelial crypts and tumors. In human colonic PCmsrc cells transformed by c-src oncogene, the hepatocyte growth factor (HGF)-dependent invasiveness of collagen gels was abolished by 0.1 microM PAF and restored by the PAF-R antagonists WEB2086 and SR27417. PAF blocked HGF-induced tyrosine phosphorylation of p125 focal adhesion kinase. The phosphatidylinositol 3'-kinase (PI3'-K) inhibitors wortmannin and LY294002 totally blocked the HGF-induced invasion. Similar effects were observed in ts-srcMDCK kidney epithelial cells transformed by a v-Src temperature-sensitive mutant: (i) PAF and wortmannin exerted additive inhibitory effects on Src-induced invasion and (ii) activated and dominant negative forms of p110alpha PI3'-K, respectively, amplified and abrogated the Src- and HGF-dependent invasiveness of parental and ts-srcMDCK cells. We also provided the first evidence for the contribution of rapamycin-insensitive, pertussis toxin-dependent G-protein pathways to the integration of the signals emerging from activated Met and PAF receptors. These results indicate that PI3'-K is a critical transducer of invasiveness and strongly suggest that PAF exerts a negative control on invasion by inhibiting this signaling pathway. A possible beneficial role of PAF analogs on tumor invasion is therefore proposed.
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PMID:Inhibition by platelet-activating factor of Src- and hepatocyte growth factor-dependent invasiveness of intestinal and kidney epithelial cells. Phosphatidylinositol 3'-kinase is a critical mediator of tumor invasion. 960 13


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