Recently, we revealed that the tyrosine kinase A (TrkA) receptor plays an important role in the release of superoxides and cytokines (Oda et al. 2006, Oda et al. 2008). This review will present findings about the signal transduction via TrkA receptor induced by alpha-toxin and summarize information about its likely role in inflammatory disease, especially septic shock.
2. Role of TrkA on a inflammation induced by alpha-toxin
2.1. Signal transduction via TrkA receptor
The TrkA receptor is a 140-kDa transmembrane protein encoded by a proto-oncogene located on chromosome 1 (Martin-Zanca, Hughes and Barbacid 1986). The family of Trk receptor tyrosine kinases consists of TrkA, TrkB and TrkC. While these family members have highly conserved sequences, they are activated by different neurotrophins: TrkA by nerve growth factor (NGF), TrkB by Brain-derived neurotrophic factor (BDNF) or neurotrophin 4 (NT4), and TrkC by NT3. TrkA regulates proliferation and is important for development and maturation of the nervous system (Pierotti and Greco 2006). This receptor comprises a tyrosine-kinase domain in its intra-cytoplasmic region and five extracellular domains, including two immunoglobulin-like domains involved in NGF binding and responsible for the specific selectivity to bind NGF (Wiesmann et al. 1999). In humans, the TrkA receptor is expressed on cells throughout the nervous system (Muragaki et al. 1995) as well as on structural cells and other non-neuronal cells in the immune and neuroendocrine systems (Levi-Montalcini et al. 1995, Aloe et al. 1997, Bonini et al. 2002, Levi-Montalcini 1987). When NGF binds to the TrkA receptor, it induces receptor homodimerization, which initiates kinase activation and transphosphorylation (Kaplan et al. 1991). This kinase activation involves small G proteins (Ras, Rac, Rap-1), PLCγ, protein kinase C (PKC) and phosphatidylinositol-3 kinase (PI3K) in neural cells (Obermeier et al. 1993b, Obermeier et al. 1993a, Melamed et al. 1999, York et al. 2000, Wu, Lai and Mobley 2001). Phosphorylation at Tyr490 is required for association with Shc and activation of the Ras-MAP kinase cascade. Residues Tyr674/675 lie within the catalytic domain, and phosphorylation at this site reflects TrkA kinase activity (Segal and Greenberg 1996, Stephens et al. 1994, Obermeier et al. 1993a, Obermeier et al. 1993b, Yao and Cooper 1995). Point mutations, deletions and chromosomal rearrangements (chimeras) cause ligand-independent receptor dimerization and activation of TrkA.
The mitogen-activated protein kinase (MAPK) pathways are activated next: extracellular-regulated protein kinase (ERK) by the small G proteins; ERK, p38 and JUN-N-terminal kinase (JNK) MAPK by PKC; and p38 and JNK by PI3K (Kaplan and Miller 1997). PI3K in turn induces activation of protein kinase B (PKB or Akt) and PKCξ (York et al. 2000)(Fig. 1).
2.2. Mechanism for the superoxide generation induced by alpha-toxin
The generation of superoxide in neutrophils has been reported to be stimulated by zymosan, 12-
There are three classes of PKC isotypes: classical PKC isotypes (PKCα, -β, and -γ) which have a C1 and C2 domain, bind DG, 1-oleoyl-2-acetyl-3-phosphoglycerol (OAG) and TPA, and are regulated by DG and Ca2+; novel PKC isotypes (PKCδ, -ε, -η, and -θ), which have a C1 domain and novel C2 domain and are regulated by DG but not Ca2+; and atypical isotypes (ζ/λ), which do not bind DG and are not regulated by these classical ligands (Le Good et al. 1998). Alpha-toxin induced phosphorylation of PKCθ and PKCζ/λ, and the generation of superoxide induced by the toxin was inhibited by rottlerin and calphostin C, an inhibitor of PKCθ. We reported that the formation of DG induced by alpha-toxin in rabbit neutrophils plays an important role in the generation of superoxide (Ochi et al. 2002). It therefore appears that the toxin-induced generation of superoxide is dependent on the activation of PKCθ, through binding of PKCθ phosphorylated by PDK1 to DG (Parekh, Ziegler and Parker 2000, Toker and Newton 2000). PKCθ has been reported to play an important role in activation of the protein 1 and NF-κB signaling pathway in T cells, production of interleukin-2, and apoptosis (Altman, Isakov and Baier 2000, Fan et al. 2004, Villalba et al. 1999, Villunger et al. 1999). Our data may provide clues to the role of PKCθ in neutrophils.
We reported that the alpha-toxin-stimulated generation of superoxide was related to the formation of DG through activation of endogenous PLC by a PT-sensitive GTP-binding protein in rabbit neutrophils (Ochi et al. 2002). U73122, an inhibitor of endogenous PLC, blocked the toxin-induced generation of superoxide and formation of DG in the cells, supporting that the toxin-induced increase in superoxide is dependent on the formation of DG by endogenous PLC. However, when the level of OAG incorporated into the cells was the same as the level of DG in the cells treated with 25 nM of the toxin, the level of OAG did not induce superoxide generation in the absence of the toxin but did in the presence of a near threshold dose (2.5 nM) of the toxin which did not induce production of DG. The result shows that the toxin-induced production of superoxide requires not only the formation of DG, but also the activation of other events.
It has been reported that the PI3K signaling pathway has an important role in several effector functions including the generation of superoxide (Yamamori et al. 2004). PI3K is known to generate phosphatidylinositol 3, 4, 5-trisphosphate (PIP3), which is recognized by a pleckstrin homology domain identified as a specialized lipid-binding module (Le Good et al. 1998). Several papers have reported that PDK1 requires PIP3 as its activator for effective catalytic activity (Le Good et al. 1998). Le Good et al. reported that there is a cascade involving PI3K, PDK1, and various members of the PKC superfamily in signal transduction (Le Good et al. 1998). Furthermore, the function of PKC family members is reported to depend on the phosphorylation of an activation loop by PDK1 (Le Good et al. 1998). LY294002 and wortmannin, both PI3K inhibitors, inhibited alpha-toxin-induced generation of superoxide and phosphorylation of PDK1 but did not affect the toxin-induced formation of DG. The result shows that the toxin-induced activation of PI3K occurs upstream of the phosphorylation of PDK1, which is an important step in the toxin-induced generation of superoxide. It is likely that the toxin-induced phosphorylation of PDK1 is a process independent of the toxin-induced formation of DG.
Tyrosine phosphorylation is thought to be crucial to the regulation of effector functions in neutrophils (Rollet et al. 1994). It is known that stimuli that induce tyrosine kinase activity in cells evoke the generation of PIP1, PIP2, and PIP3. This tyrosine kinase activity is linked to the NGF receptors with intrinsic tyrosine kinase activity. Kannan et al. reported that NGF enhances the generation of superoxide induced by TPA in murine neutrophils (Kannan et al. 1991). Ehrhard et al. reported that human monocytes express the
NGF, which binds to the TrkA receptor, is reported to be required for the differentiation and survival of sympathetic and some sensory and cholinergic neuronal populations (Howe et al. 2001). Furthermore, it has been reported that NGF is involved in inflammatory responses, an increase in mast cells in neonatal rats (Woolf et al. 1996), the degranulation of rat peritoneal mast cells (Woolf et al. 1996), and the differentiation of specific granulocytes (Kannan et al. 1991). The injection of
H148G induced phosphorylation of PKCθ, but not production of DG, suggesting that the enzymatic activity of the toxin is essential for activation of endogenous PLC, but not activation of the TrkA receptor. It has been reported that binding of the C-domain, which does not contain the enzymatic site, to erythrocytes is important for the hemolysis induced by the toxin (Nagahama et al. 2002). It therefore is possible that the C-domain, the binding domain of alpha-toxin, plays a role in the binding of the toxin to the TrkA receptor and in the activation of signal transduction via the TrkA receptor.
Several studies have reported that the activation of PKC by various stimuli results in the generation of superoxide via the activation of MAPK systems (Coxon et al. 2003, Dewas et al. 2000, McLeish et al. 1998, Zu et al. 1998). K252a and U73122 inhibited the toxin-induced phosphorylation of PKCθ and ERK1/2 and generation of superoxide, suggesting that the toxin-induced production of superoxide is linked to the stimulation of the MAPK system via the activation of PKCθ. The toxin causes phosphorylation of ERK1/2, but not p38 and SAPK/JNK, implying that the process is dependent on a MAPK system containing MEK1/2 and MAPK/ERK1/2, but not systems containing p38 and SAPK/JNK.
It has been reported that PA directly or indirectly activated NADPH oxidase in a cell-free system of neutrophils (Erickson et al. 1999) and that PKCδ regulates phosphorylation of p67phox in human monocytes (Zhao et al. 2005). PKC also has been reported to activate directly NADPH oxidase (Johnson et al. 1998). However, PD98059 almost completely inhibited the toxin-induced production of superoxide near the inhibitory threshold dose of the inhibitor. Thus, it is unlikely that PA and PKC directly activate NADPH oxidase under the conditions used here.
We have shown that alpha-toxin induces formation of DG through the activation of endogenous PLC by a PT-sensitive GTP-binding protein and phosphorylation of PDK1 via stimulation of the TrkA receptor, so that DG and PDK1 synergistically activate PKCθ, and that the activation of PKCθ stimulates generation of superoxide through MAPK-associated signaling events in rabbit neutrophils (Fig. 2).
2.3. Mechanism for the cytokine release induced by alpha-toxin
Cytokines are immunoregulatory peptides with a potent inflammatory action, mediating the immune/metabolic response to an external noxious stimulus and fueling the transition from sepsis to septic shock, multiple organ dysfunction syndromes, and/or multiple organ failure (Tracey et al. 1987, Dinarello 2004, Riedemann, Guo and Ward 2003). It is thought that synergistic interactions between cytokines can cause or attenuate tissue injury (Calandra, Bochud and Heumann 2002). TNF-α, which is released early from neutrophils and macrophages, is one of the important cytokines involved in the pathophysiology of sepsis (Tracey et al. 1987, Lum et al. 1999). TNF-α-induced tissue injury is largely mediated through neutrophils, that respond by producing elastase, superoxide ion, hydrogen
peroxide, sPLA2, PAF, leukotriene B1, and thromboxane A2 (Aldridge 2002). IL-1 stimulates the synthesis and release of prostagrandins, elastases, and collagenases and transendothelial microvascular cells, which respond by releasing the powerful neutrophil-stimulating agents, PAF and IL-8 (Leirisalo-Repo 1994). IL-1 and TNF-α are synergistic and share many biological effects in sepsis (Herbertson et al. 1995).
Anti-TNF-α antibody inhibited the death of mice induced by alpha-toxin. Furthermore, TNF-α-deficient mice were resistant to alpha-toxin. These observations suggest that the lethal effect of alpha-toxin is closely related to the release of TNF-α into the bloodstream. Stevens et al. and Bunting et al. suggested that alpha-toxin contributes indirectly to shock by stimulating production of endogenous mediators such as TNF-α and platelet-activating factor (Bunting et al. 1997, Stevens and Bryant 1997). It therefore appears that TNF-α released by alpha-toxin is important in enhancing the toxic actions of alpha-toxin in vivo. Consequently, inhibitors for release and expression of TNF-α may be worth pursuing as a novel therapeutic approach to the treatment of gas gangrene and sepsis caused by
Cytokines such as the pro-inflammatory TNF-α, interleukin-1β (IL-1β) or transforming growth factor-β (TGF-β), increase the synthesis of NGF in airway structural cells. This stimulation has been evidenced in vitro in human pulmonary fibroblasts (Olgart and Frossard 2001, Micera et al. 2001), A549 epithelial cells (Pons et al. 2001) and bronchial smooth muscle cells (Freund et al. 2002). Studies also show that pro-inflammatory cytokines can act in concert to stimulate additional NGF secretion: TNF-α, for example, increases the secretion of NGF induced by IL-1β and interferon γ (IFN-γ) in fibroblasts (Hattori et al. 1994) and by interleukin-4 (IL-4) in astrocytes (Brodie et al. 1998). NGF synthesis in inflammatory conditions has also been demonstrated in vivo: elevated NGF concentrations are observed in cutaneous inflammation (Safieh-Garabedian et al. 1995) and in asthmatic airways (Olgart and Frossard 2001, Kassel, da Silva and Frossard 2001, Virchow et al. 1998). Taken together, these results suggest that pro-inflammatory cytokines, which are present at high levels in the airways of patients with asthma (Tillie-Leblond et al. 1999), might contribute to the elevated levels of NGF synthesis.
Corticosteroids are well known for their anti-inflammatory properties, particularly in asthmatic airways. Numerous studies report that the glucocorticoids dexamethasone and budesonide affect NGF expression. They cause a significant reduction in the increased NGF expression induced by pro-inflammatory cytokines; in one study, this action was shown to result from the repression of NGF gene transcription in endoneural fibroblasts from the rat sciatic nerve (Lindholm et al. 1990). Olgart and Frossard have reported that glucocorticoid treatment decreases the NGF secretion that the pro-inflammatory cytokines IL-1β and TNF-α stimulate in cultures of human pulmonary fibroblasts (Olgart and Frossard 2001) and in A549 epithelial cells (Pons et al. 2001).
These results suggested that the initial release of pro-inflammatory cytokines induced by alpha-toxin in vivo leads to the production of NGF, and the NGF released synergistically causes systemic inflammation such as sepsis and shock via activation of the TrkA receptor (Fig. 3).
Aldridge A. J. 2002 Role of the neutrophil in septic shock and the adult respiratory distress syndromeEur J Surg, 168 204 14
Aloe L. Bracci-Laudiero L. Bonini S. Manni L. 1997 The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases. 52 883 94
Altman A. Isakov N. Baier G. 2000 Protein kinase Ctheta: a new essential superstar on the T-cell stage.Immunol Today, 21 567 73
Awad M. M. Bryant A. E. Stevens D. L. Rood J. I. 1995 Virulence studies on chromosomal alpha-toxin and theta-toxin mutants constructed by allelic exchange provide genetic evidence for the essential role of alpha-toxin in Clostridium perfringens-mediated gas gangrene.Mol Microbiol, 15 191 202
Babior B. M. 1999 NADPH oxidase: an update. 93 1464 76
Bellavite P. Corso F. Dusi S. Grzeskowiak M. Della -Bianca V. Rossi F. 1988 Activation of NADPH-dependent superoxide production in plasma membrane extracts of pig neutrophils by phosphatidic acid.J Biol Chem, 263 8210 4
Bonini S. Lambiase A. Lapucci G. Properzi F. Bresciani M. Bracci M. L. Laudiero M. J. Mancini A. Procoli A. Micera G. Sacerdoti F. Levi-Schaffer G. Rasi Aloe L. 2002Nerve growth factor and asthma. Allergy, 57 Suppl 72 13 5
Brodie C. Goldreich N. Haiman T. Kazimirsky G. 1998 Functional IL-4 receptors on mouse astrocytes: IL-4 inhibits astrocyte activation and induces NGF secretion.J Neuroimmunol, 81 20 30
Bryant A. E. Chen R. Y. Nagata Y. Wang Y. Lee C. H. Finegold S. Guth P. H. Stevens D. L. 2000aClostridial gas gangrene. I. Cellular and molecular mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens. J Infect Dis, 182 799 807
Bryant A. E. Chen R. Y. Nagata Y. Wang Y. Lee C. H. Finegold S. Guth P. H. Stevens D. L. 2000bClostridial gas gangrene. II. Phospholipase C-induced activation of platelet gpIIbIIIa mediates vascular occlusion and myonecrosis in Clostridium perfringens gas gangrene. J Infect Dis, 182 808 15
Bunting M. Lorant D. E. Bryant A. E. Zimmerman G. A. Mc Intyre T. M. Stevens D. L. Prescott S. M. 1997Alpha toxin from Clostridium perfringens induces proinflammatory changes in endothelial cells. J Clin Invest, 100 565 74
Calandra T. Bochud P. Y. Heumann D. 2002Cytokines in septic shock. Curr Clin Top Infect Dis, 22 1 23
Coxon P. Y. Rane M. J. Uriarte S. Powell D. W. Singh S. Butt W. Chen Q. Mc Leish K. R. 2003MAPK-activated protein kinase-2 participates in 38MAPK-dependent and ERK-dependent functions in human neutrophils. Cell Signal, 15, 993-1001.
Dewas C. Fay M. Gougerot-Pocidalo M. A. El -Benna J. 2000 The mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 pathway is involved in formyl-methionyl-leucyl-phenylalanine-inducedJ Immunol, 165, 5238-44. 47phoxphosphorylation in human neutrophils.
Dinarello C. A. 2004 Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation.Curr Opin Pharmacol, 4 378 85
Ehrhard P. B. Ganter U. Stalder A. Bauer J. Otten U. 1993 Expression of functional trk protooncogene in human monocytes.Proc Natl Acad Sci U S A, 90 5423 7
Erickson R. W. Langel-Peveri P. Traynor-Kaplan A. E. Heyworth P. G. Curnutte J. T. 1999 Activation of human neutrophil NADPH oxidase by phosphatidic acid or diacylglycerol in a cell-free system. Activity of diacylglycerol is dependent on its conversion to phosphatidic acid.J Biol Chem, 274 22243 50
Fan Y. Y. Ly L. H. Barhoumi R. Mc Murray D. N. Chapkin R. S. 2004 Dietary docosahexaenoic acid suppresses T cell protein kinase C theta lipid raft recruitment and IL-2 production.J Immunol, 173 6151 60
Freund V. Pons F. Joly V. Mathieu E. Martinet N. Frossard N. 2002 Upregulation of nerve growth factor expression by human airway smooth muscle cells in inflammatory conditions.Eur Respir J, 20 458 63
Garland L. G. 1992 New pathways of phagocyte activation: the coupling of receptor-linked phospholipase D and the role of tyrosine kinase in primed neutrophils.FEMS Microbiol Immunol, 5 229 37
Hattori A. Iwasaki S. Murase K. Tsujimoto M. Sato M. Hayashi K. Kohno M. 1994 Tumor necrosis factor is markedly synergistic with interleukin 1 and interferon-gamma in stimulating the production of nerve growth factor in fibroblasts.FEBS Lett, 340 177 80
Herbertson M. J. Werner H. A. Goddard C. M. Russell J. A. Wheeler A. Coxon R. Walley K. R. 1995Anti-tumor necrosis factor-alpha prevents decreased ventricular contractility in endotoxemic pigs. Am J Respir Crit Care Med, 152 480 8
Howe C. L. Valletta J. S. Rusnak A. S. Mobley W. C. 2001 NGF signaling from clathrin-coated vesicles: evidence that signaling endosomes serve as a platform for the Ras-MAPK pathway. 32 801 14
Johnson J. L. Park J. W. Benna J. E. Faust L. P. Inanami O. Babior B. M. 1998Activation of 47PHOX), a cytosolic subunit of the leukocyte NADPH oxidase. Phosphorylation of ser-359 or ser-370 precedes phosphorylation at other sites and is required for activity. J Biol Chem, 273, 35147-52.
Kannan Y. Ushio H. Koyama H. Okada M. Oikawa M. Yoshihara T. Kaneko M. Matsuda H. 1991S nerve growth factor enhances survival, phagocytosis, and superoxide production of murine neutrophils. Blood, 77 1320 5
Kaplan D. R. Hempstead B. L. Martin-Zanca D. Chao M. V. Parada L. F. 1991 The trk proto-oncogene product: a signal transducing receptor for nerve growth factor.Science, 252 554 8
Kaplan D. R. Miller F. D. 1997 Signal transduction by the neurotrophin receptors.Curr Opin Cell Biol, 9 213 21
Kassel O. da C. Silva Frossard N. 2001The stem cell factor, its properties and potential role in the airways. Pulm Pharmacol Ther, 14 277 88
Kusunoki T. Higashi H. Hosoi S. Hata D. Sugie K. Mayumi M. Mikawa H. 1992 Tyrosine phosphorylation and its possible role in superoxide production by human neutrophils stimulated with FMLP and IgG.Biochem Biophys Res Commun, 183 789 96
Le Good J. A. Ziegler W. H. Parekh D. B. Alessi D. R. Cohen P. Parker P. J. 1998Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science, 281 2042 5
Leirisalo-Repo M. 1994 The present knowledge of the inflammatory process and the inflammatory mediators.Pharmacol Toxicol, 75 Suppl 2 1 3
Levi-Montalcini R. 1987 The nerve growth factor 35 years later.Science, 237 1154 62
Levi-Montalcini R. Dal R. Toso F. della Valle S. D. Skaper Leon A. 1995Update of the NGF saga. J Neurol Sci, 130 119 27
Lindholm D. Hengerer B. Heumann R. Carroll P. Thoenen H. 1990 Glucocorticoid Hormones Negatively Regulate Nerve Growth Factor Expression In Vivo and in Cultured Rat FibroblastsEur J Neurosci, 2 795 801
Lum L. Wong B. R. Josien R. Becherer J. D. Erdjument-Bromage H. Schlondorff J. Tempst P. Choi Y. Blobel C. P. 1999Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem, 274 13613 8
Martin-Zanca D. Hughes S. H. Barbacid M. 1986 A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. 319 743 8
Mc Leish K. R. Knall C. Ward R. A. Gerwins P. Coxon P. Y. Klein J. B. Johnson G. L. 1998 Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-alpha and GM-CSF.J Leukoc Biol, 64 537 45
Melamed I. Patel H. Brodie C. Gelfand E. W. 1999 Activation of Vav and Ras through the nerve growth factor and B cell receptors by different kinases.Cell Immunol, 191 83 9
Micera A. Vigneti E. Pickholtz D. Reich R. Pappo O. Bonini S. Maquart F. X. Aloe L. Levi-Schaffer F. 2001 Nerve growth factor displays stimulatory effects on human skin and lung fibroblasts, demonstrating a direct role for this factor in tissue repairProc Natl Acad Sci U S A, 98 6162 7
Mitsuyama T. Takeshige K. Minakami S. 1993 Tyrosine phosphorylation is involved in the respiratory burst of electropermeabilized human neutrophils at a step before diacylglycerol formation by phospholipase C.FEBS Lett, 322 280 4
Muragaki Y. Timothy N. Leight S. Hempstead B. L. Chao M. V. Trojanowski J. Q. Lee V. M. 1995 Expression of trk receptors in the developing and adult human central and peripheral nervous system.J Comp Neurol, 356 387 97
Nagahama M. Mukai M. Morimitsu S. Ochi S. Sakurai J. 2002 Role of the C-domain in the biological activities of Clostridium perfringens alpha-toxin.Microbiol Immunol, 46 647 55
Nick J. A. Avdi N. J. Young S. K. Knall C. Gerwins P. Johnson G. L. Worthen G. S. 1997 Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.J Clin Invest, 99 975 86
Obermeier A. Halfter H. Wiesmuller K. H. Jung G. Schlessinger J. Ullrich A. 1993aTyrosine 785 is a major determinant of Trk--substrate interaction. EMBO J, 12 933 41
Obermeier A. Lammers R. Wiesmuller K. H. Jung G. Schlessinger J. Ullrich A. 1993b Identification of Trk binding sites for SHC and phosphatidylinositol 3’-kinase and formation of a multimeric signaling complex.J Biol Chem, 268 22963 6
Ochi S. Hashimoto K. Nagahama M. Sakurai J. 1996 Phospholipid metabolism induced by Clostridium perfringens alpha-toxin elicits a hot-cold type of hemolysis in rabbit erythrocytes.Infect Immun, 64 3930 3
Ochi S. Miyawaki T. Matsuda H. Oda M. Nagahama M. Sakurai J. 2002Clostridium perfringens alpha-toxin induces rabbit neutrophil adhesion. Microbiology, 148 237 45
Ochi S. Oda M. Matsuda H. Ikari S. Sakurai J. 2004 Clostridium perfringens alpha-toxin activates the sphingomyelin metabolism system in sheep erythrocytes.J Biol Chem, 279 12181 9
Oda M. Ikari S. Matsuno T. Morimune Y. Nagahama M. Sakurai J. 2006 Signal transduction mechanism involved in Clostridium perfringens alpha-toxin-induced superoxide anion generation in rabbit neutrophils.Infect Immun, 74 2876 86
Oda M. Matsuno T. Shiihara R. Ochi S. Yamauchi R. Saito Y. Imagawa H. Nagahama M. Nishizawa M. Sakurai J. 2008 The relationship between the metabolism of sphingomyelin species and the hemolysis of sheep erythrocytes induced by Clostridium perfringens alpha-toxin.J Lipid Res, 49 1039 47
Olgart C. Frossard N. 2001 Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids.Eur Respir J, 18 115 21
Olson S. C. Tyagi S. R. Lambeth J. D. 1990Fluoride activates diradylglycerol and superoxide generation in human neutrophils via PLD/PA phosphohydrolase-dependent and-independent pathways. FEBS Lett, 272 19 24
Parekh D. B. Ziegler W. Parker P. J. 2000 Multiple pathways control protein kinase C phosphorylation.EMBO J, 19 496 503
Pierotti M. A. Greco A. 2006 Oncogenic rearrangements of the NTRK1/NGF receptorCancer Lett, 232 90 8
Pongracz J. Lord J. M. 1998 Superoxide production in human neutrophils: evidence for signal redundancy and the involvement of more than one PKC isoenzyme class.Biochem Biophys Res Commun, 247 624 9
Pons F. Freund V. Kuissu H. Mathieu E. Olgart C. Frossard N. 2001 Nerve growth factor secretion by human lung epithelial A549 cells in pro- and anti-inflammatory conditions.Eur J Pharmacol, 428 365 9
Riedemann N. C. Guo R. F. Ward P. A. 2003 Novel strategies for the treatment of sepsis.Nat Med, 9 517 24
Rollet E. Caon A. C. Roberge C. J. Liao N. W. Malawista S. E. Mc Coll S. R. Naccache P. H. 1994 Tyrosine phosphorylation in activated human neutrophils. Comparison of the effects of different classes of agonists and identification of the signaling pathways involved.J Immunol, 153 353 63
Safieh-Garabedian B. Poole S. Allchorne A. Winter J. Woolf C. J. 1995 Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia.Br J Pharmacol, 115 1265 75
Sakurai J. Nagahama M. Oda M. 2004 Clostridium perfringens alpha-toxin: characterization and mode of actionJ Biochem, 136 569 74
Segal R. A. Greenberg M. E. 1996 Intracellular signaling pathways activated by neurotrophic factors.Annu Rev Neurosci, 19 463 89
Shenoy N. G. Gleich G. J. Thomas L. L. 2003 Eosinophil major basic protein stimulates neutrophil superoxide production by a class IA phosphoinositide 3-kinase and protein kinase C-zeta-dependent pathway.J Immunol, 171 3734 41
Stephens R. M. Loeb D. M. Copeland T. D. Pawson T. Greene L. A. Kaplan D. R. 1994 Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. 12 691 705
Stevens D. L. Bryant A. E. 1997 Pathogenesis of Clostridium perfringens infection: mechanisms and mediators of shock.Clin Infect Dis, 25 Suppl 2, S 160 4
Tillie-Leblond I. Pugin J. Marquette C. H. Lamblin C. Saulnier F. Brichet A. Wallaert B. Tonnel A. B. Gosset P. 1999 Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmaticus.Am J Respir Crit Care Med, 159 487 94
Toker A. Newton A. C. 2000 Cellular signaling: pivoting around PDK-1. 103 185 8
Tracey K. J. Fong Y. Hesse D. G. Manogue K. R. Lee A. T. Kuo G. C. Lowry S. F. Cerami A. 1987Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature, 330 662 4
Villalba M. Kasibhatla S. Genestier L. Mahboubi A. Green D. R. Altman A. 1999 Protein kinase ctheta cooperates with calcineurin to induce Fas ligand expression during activation-induced T cell death.J Immunol, 163 5813 9
Villunger A. Ghaffari-Tabrizi N. Tinhofer I. Krumbock N. Bauer B. Schneider T. Kasibhatla S. Greil R. Baier-Bitterlich G. Uberall F. Green D. R. Baier G. 1999 Synergistic action of protein kinase C theta and calcineurin is sufficient for Fas ligand expression and induction of a crmA-sensitive apoptosis pathway in Jurkat T cells.Eur J Immunol, 29 3549 61
Virchow J. C. Julius P. Lommatzsch M. Luttmann W. Renz H. Braun A. 1998 Neurotrophins are increased in bronchoalveolar lavage fluid after segmental allergen provocation.Am J Respir Crit Care Med, 158 2002 5
Wiesmann C. Ultsch M. H. Bass S. H. de Vos A. M. 1999 Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. 401 184 8
Williamson E. D. Titball R. W. 1993 A genetically engineered vaccine against the alpha-toxin of Clostridium perfringens protects mice against experimental gas gangrene. 11 1253 8
Woolf C. J. Ma Allchorne Q. P. A. Poole S. 1996 Peripheral cell types contributing to the hyperalgesic action of nerve growth factor in inflammation.J Neurosci, 16 2716 23
Wu C. Lai C. F. Mobley W. C. 2001 Nerve growth factor activates persistent Rap1 signaling in endosomes.J Neurosci, 21 5406 16
Yamamori T. Inanami O. Nagahata H. Kuwabara M. 2004Phosphoinositide 3-kinase regulates the phosphorylation of NADPH oxidase component 47phox) by controlling cPKC/PKCdelta but not Akt. Biochem Biophys Res Commun, 316, 720-30.
Yao R. Cooper G. M. 1995 Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor.Science, 267 2003 6
Yasaka T. Boxer L. A. Baehner R. L. 1982 Monocyte aggregation and superoxide anion release in response to formyl-methionyl-leucyl-phenylalanine (FMLP) and platelet-activating factor (PAF).J Immunol, 128 1939 44
York R. D. Molliver D. C. Grewal S. S. Stenberg P. E. Mc Cleskey E. W. Stork P. J. 2000 Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rap1.Mol Cell Biol, 20 8069 83
Zhao X. Xu B. Bhattacharjee A. Oldfield C. M. Wientjes F. B. Feldman G. M. Cathcart M. K. 2005Protein kinase Cdelta regulates 67phoxphosphorylation in human monocytes. J Leukoc Biol, 77, 414-20.
Zu Y. L. Qi J. Gilchrist A. Fernandez G. A. Vazquez-Abad D. Kreutzer D. L. Huang C. K. Sha’afi R. I. 1998 38mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation. J Immunol, 160, 1982-9.