Inhibitory action of Lipoxins on Superoxide production in neutrophils

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Inhibitory action of Lipoxins on Superoxide production in neutrophils

Deregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways in cystic fibrosis (CF). In normal tissues, the lipoxins are endogenous anti-inflammatory lipid mediators that are important regulators of neutrophilic inflammation [1]. In CF, the generation of lipoxins is impaired [2], [3].

In response to infection or tissue injury, arachidonic acid produces proinflammatory Leukotriene B4 that leads to neutrophil recruitment and acute inflammation [4], [5], [6].

Arachidonic acid also produces antiinflammatory lipoxins. Lipoxins mediate switch to chronic inflammation and promote resolution [6], [7], [8]. In CF, inflammatory response remains persistently neutrophilic (acute inflammation) that leads to tissue injury and further infection. This may be attributed to a documented defect in the generation of lipoxins [1], [2], [3].

Lipoxins are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, lipoxins (Lipoxin A4, 15-epi-LXA4 and its stable synthetic analog 15-epi-p-fluoro-phenoxy-LXA4) display potent antiinflammatory actions, including attenuation of neutrophil respiratory burst and transendothelial migration [1], [9].

Leukotriene B4 and Lipoxins (Lipoxin A4, 15-epi-LXA4 and 15-epi-p-fluoro-phenoxy-LXA4) interact with highly specific and distinct G protein-coupled membrane receptors [10], [11], [12], to evoke opposing leukocyte responses, including Lipoxin A4 inhibition of Leukotriene B4-initiated respiratory burst, chemotaxis, adhesion, and transmigration [13].

Leukotriene B4 binds to the Leukotriene B4 receptor (LTBR1) which activates both Phospholipase C beta 2 (PLC-beta2) and Phosphatidylinositol 3-kinase (PI3K reg class IB (p101) and PI3K cat class IB (p110-gamma)) signaling via G-protein alpha-i family, G-protein alpha-15 and G-protein beta/gamma subunits [4], [11], [14], [15], [16], [17], [18].

PLC-beta2 catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates Ca(2+) release from endoplasmic reticulum. Ca(2+) and DAG, in turn, activate Protein kinase C alpha (PKC-alpha). Phosphatidylinositol 3-kinase phosphorylates the membrane lipid PtdIns(4,5)P2 to phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) [14], [16], [19], [20], [21]. PtdIns(3,4,5)P3 recruits and activates diverse cytosolic effectors, including Phospholipase D1 (PLD1) [22], 3-phosphoinositide dependent protein kinase-1 (PDPK1) [23], [24], Protein kinase C zeta (PKC-zeta) [25] and Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 (PREX1) [26], [27]. PREX1 is the main guanine nucleotide exchange factor for the Ras-related C3 botulinum toxin substrate 2 (RAC2) in neutrophils [28], [29], [30].

Interleukin-8 (IL-8) is probably involved in the release of reactive oxygen species (ROS) by neutrophils. IL-8-induced activation of the respiratory burst is exclusively mediated by Interleukin 8 receptor alpha (IL8RA), and does not involve PLC-beta and calcium signaling [31], [32], [33].

Lipoxin A4, 15-epi-LXA4 and 15-epi-p-fluoro-phenoxy-LXA4 interact with the Formyl peptide receptor-like 1 (FPRL1) [1], [7], [8], [12] that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to Presqualene monophosphate upon cell activation. Phosphatidic acid phosphatase type 2 domain containing 2 (PPAPDC2) is a presqualene diphosphate phosphatase that converts Presqualene diphosphate to Presqualene monophosphate [34]. In human, neutrophils leukotriene-induced LTBR1 signaling initiates a rapid decrease in Presqualene diphosphate levels, probably through PPADC2 activation, to promote proinflammatory cell response, whereas lipoxin-induced FPRL1 signaling dramatically blocks Presqualene diphosphate turnover to Presqualene monophosphate, probably through PPADC2 inhibition, to prevent neutrophil activation [6], [35].

Presqualene diphosphate, but not Presqualene monophosphate, directly inhibits PI3K cat class IB (p110-gamma) and Phospholipase D1 (PLD1), preventing subsequent NADPH oxidase assembly and superoxide anion generation [6], [35], [36], [37], [38], [39].

Downstream of Phosphatidylinositol 3-kinase signaling PDPK1 can phosphorylate and activate PKC-zeta and PKC-alpha [40], [41], [42], [43], [44].

PLD1 hydrolyzes membrane Phosphatidylcholines to generate Phosphatidic acid that is a powerful activator of PKC-zeta, which is, together with PKC-alpha, involved in phosphorylation of NADPH oxidase complex subunits [45], [46], [47], [48], [49].

The NADPH oxidase is a multicomponent enzyme in which cytosolic regulatory components (Neutrophil cytosolic factors 1, 2 and 4 (p47-phox, p67-phox and p40-phox)) must assembly with membrane-ancored Cytochrome b-558 that is composed of two transmembrane catalytic subunits, alpha (p22-phox) and beta (gp91-phox). The NADPH oxidase catalyzes the NADPH-dependent one electron reduction of O(2) to form superoxide anion (O(2)(-), from which other reactive oxygen species, including hydrogen peroxide, hydroxyl radical, and hypochlorous acid, are derived [30].

The neutrophil NADPH oxidase assembly is directly regulated by PKC-zeta, PKC-alpha [48], [49], [50], RAC2 [30], [51] and its effector, p21/Cdc42/Rac1-activated kinase 1 (PAK1) [52], [53], [54].

References:

  1. Karp CL, Flick LM, Yang R, Uddin J, Petasis NA
    Cystic fibrosis and lipoxins. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):263-70
  2. Karp CL, Flick LM, Park KW, Softic S, Greer TM, Keledjian R, Yang R, Uddin J, Guggino WB, Atabani SF, Belkaid Y, Xu Y, Whitsett JA, Accurso FJ, Wills-Karp M, Petasis NA
    Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nature immunology 2004 Apr;5(4):388-92
  3. Takai D, Nagase T, Shimizu T
    New therapeutic key for cystic fibrosis: a role for lipoxins. Nature immunology 2004 Apr;5(4):357-8
  4. Ito N, Yokomizo T, Sasaki T, Kurosu H, Penninger J, Kanaho Y, Katada T, Hanaoka K, Shimizu T
    Requirement of phosphatidylinositol 3-kinase activation and calcium influx for leukotriene B4-induced enzyme release. The Journal of biological chemistry 2002 Nov 22;277(47):44898-904
  5. Chmiel JF, Davis PB
    State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection? Respiratory research 2003;4:8
  6. Bonnans C, Levy BD
    Lipid mediators as agonists for the resolution of acute lung inflammation and injury. American journal of respiratory cell and molecular biology 2007 Feb;36(2):201-5
  7. Chiang N, Arita M, Serhan CN
    Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):163-77
  8. Serhan CN
    Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual review of immunology 2007;25:101-37
  9. Filep JG, Khreiss T, Jozsef L
    Lipoxins and aspirin-triggered lipoxins in neutrophil adhesion and signal transduction. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):257-62
  10. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN
    Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. The Journal of experimental medicine 1997 May 5;185(9):1693-704
  11. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T
    A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997 Jun 5;387(6633):620-4
  12. El Kebir D, Jozsef L, Khreiss T, Pan W, Petasis NA, Serhan CN, Filep JG
    Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation. Journal of immunology (Baltimore, Md. : 1950) 2007 Jul 1;179(1):616-22
  13. Serhan CN
    Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):141-62
  14. Gaudreau R, Le Gouill C, Metaoui S, Lemire S, Stankova J, Rola-Pleszczynski M
    Signalling through the leukotriene B4 receptor involves both alphai and alpha16, but not alphaq or alpha11 G-protein subunits. The Biochemical journal 1998 Oct 1;335 ( Pt 1):15-8
  15. Gaudreau R, Le Gouill C, Venne MH, Stankova J, Rola-Pleszczynski M
    Threonine 308 within a putative casein kinase 2 site of the cytoplasmic tail of leukotriene B(4) receptor (BLT1) is crucial for ligand-induced, G-protein-coupled receptor-specific kinase 6-mediated desensitization. The Journal of biological chemistry 2002 Aug 30;277(35):31567-76
  16. Niggli V
    Signaling to migration in neutrophils: importance of localized pathways. The international journal of biochemistry & cell biology 2003 Dec;35(12):1619-38
  17. Hou C, Kirchner T, Singer M, Matheis M, Argentieri D, Cavender D
    In vivo activity of a phospholipase C inhibitor, 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), in acute and chronic inflammatory reactions. The Journal of pharmacology and experimental therapeutics 2004 May;309(2):697-704
  18. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  19. Goldman DW, Chang FH, Gifford LA, Goetzl EJ, Bourne HR
    Pertussis toxin inhibition of chemotactic factor-induced calcium mobilization and function in human polymorphonuclear leukocytes. The Journal of experimental medicine 1985 Jul 1;162(1):145-56
  20. Andersson T, Schlegel W, Monod A, Krause KH, Stendahl O, Lew DP
    Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1,4,5-trisphosphate. A second messenger for Ca2+ mobilization. The Biochemical journal 1986 Dec 1;240(2):333-40
  21. Lew PD, Dayer JM, Wollheim CB, Pozzan T
    Effect of leukotriene B4, prostaglandin E2 and arachidonic acid on cytosolic-free calcium in human neutrophils. FEBS letters 1984 Jan 23;166(1):44-8
  22. Lee JS, Kim JH, Jang IH, Kim HS, Han JM, Kazlauskas A, Yagisawa H, Suh PG, Ryu SH
    Phosphatidylinositol (3,4,5)-trisphosphate specifically interacts with the phox homology domain of phospholipase D1 and stimulates its activity. Journal of cell science 2005 Oct 1;118(Pt 19):4405-13
  23. Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J
    Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. The Biochemical journal 1999 Feb 1;337 ( Pt 3):575-83
  24. Di Paolo G, De Camilli P
    Phosphoinositides in cell regulation and membrane dynamics. Nature 2006 Oct 12;443(7112):651-7
  25. Nakanishi H, Brewer KA, Exton JH
    Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. The Journal of biological chemistry 1993 Jan 5;268(1):13-6
  26. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR
    P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 2002 Mar 22;108(6):809-21
  27. Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC, Hawkins PT, Stephens LR
    Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. The Journal of biological chemistry 2005 Feb 11;280(6):4166-73
  28. Welch HC, Condliffe AM, Milne LJ, Ferguson GJ, Hill K, Webb LM, Okkenhaug K, Coadwell WJ, Andrews SR, Thelen M, Jones GE, Hawkins PT, Stephens LR
    P-Rex1 regulates neutrophil function. Current biology : CB 2005 Oct 25;15(20):1867-73
  29. Hill K, Welch HC
    Purification of P-Rex1 from neutrophils and nucleotide exchange assay. Methods in enzymology 2006;406:26-41
  30. Bokoch GM, Zhao T
    Regulation of the phagocyte NADPH oxidase by Rac GTPase. Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1533-48
  31. Jones SA, Wolf M, Qin S, Mackay CR, Baggiolini M
    Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. Proceedings of the National Academy of Sciences of the United States of America 1996 Jun 25;93(13):6682-6
  32. Asagoe K, Yamamoto K, Takahashi A, Suzuki K, Maeda A, Nohgawa M, Harakawa N, Takano K, Mukaida N, Matsushima K, Okuma M, Sasada M
    Down-regulation of CXCR2 expression on human polymorphonuclear leukocytes by TNF-alpha. Journal of immunology (Baltimore, Md. : 1950) 1998 May 1;160(9):4518-25
  33. Mukaida N
    Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. American journal of physiology. Lung cellular and molecular physiology 2003 Apr;284(4):L566-77
  34. Fukunaga K, Arita M, Takahashi M, Morris AJ, Pfeffer M, Levy BD
    Identification and functional characterization of a presqualene diphosphate phosphatase. The Journal of biological chemistry 2006 Apr 7;281(14):9490-7
  35. Levy BD, Fokin VV, Clark JM, Wakelam MJ, Petasis NA, Serhan CN
    Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A4. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999 May;13(8):903-11
  36. Levy BD, Serhan CN
    A novel polyisoprenyl phosphate signaling cascade in human neutrophils. Annals of the New York Academy of Sciences 2000 Apr;905:69-80
  37. Levy BD, Serhan CN
    Polyisoprenyl phosphates: natural antiinflammatory lipid signals. Cellular and molecular life sciences : CMLS 2002 May;59(5):729-41
  38. Levy BD, Hickey L, Morris AJ, Larvie M, Keledjian R, Petasis NA, Bannenberg G, Serhan CN
    Novel polyisoprenyl phosphates block phospholipase D and human neutrophil activation in vitro and murine peritoneal inflammation in vivo. British journal of pharmacology 2005 Oct;146(3):344-51
  39. Bonnans C, Fukunaga K, Keledjian R, Petasis NA, Levy BD
    Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury. The Journal of experimental medicine 2006 Apr 17;203(4):857-63
  40. Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A
    Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Current biology : CB 1998 Sep 24;8(19):1069-77
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    A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1. The Journal of biological chemistry 2000 Jul 7;275(27):20806-13
  42. Sonnenburg ED, Gao T, Newton AC
    The phosphoinositide-dependent kinase, PDK-1, phosphorylates conventional protein kinase C isozymes by a mechanism that is independent of phosphoinositide 3-kinase. The Journal of biological chemistry 2001 Nov 30;276(48):45289-97
  43. Hodgkinson CP, Sale GJ
    Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment. Biochemistry 2002 Jan 15;41(2):561-9
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    Phosphatidylinositol 3-kinase gamma signaling through protein kinase Czeta induces NADPH oxidase-mediated oxidant generation and NF-kappaB activation in endothelial cells. The Journal of biological chemistry 2006 Jun 9;281(23):16128-38
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    Phosphatidylcholine hydrolysis by phospholipase D determines phosphatidate and diglyceride levels in chemotactic peptide-stimulated human neutrophils. Involvement of phosphatidate phosphohydrolase in signal transduction. The Journal of biological chemistry 1989 Oct 15;264(29):17069-77
  46. Limatola C, Schaap D, Moolenaar WH, van Blitterswijk WJ
    Phosphatidic acid activation of protein kinase C-zeta overexpressed in COS cells: comparison with other protein kinase C isotypes and other acidic lipids. The Biochemical journal 1994 Dec 15;304 ( Pt 3):1001-8
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    Interleukin 1-beta-induced protein kinase C-zeta activation is mimicked by exogenous phospholipase D. The Biochemical journal 1997 Jan 15;321 ( Pt 2):497-501
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    Protein kinase C zeta phosphorylates a subset of selective sites of the NADPH oxidase component p47phox and participates in formyl peptide-mediated neutrophil respiratory burst. Journal of immunology (Baltimore, Md. : 1950) 2001 Jan 15;166(2):1206-13
  49. Fontayne A, Dang PM, Gougerot-Pocidalo MA, El-Benna J
    Phosphorylation of p47phox sites by PKC alpha, beta II, delta, and zeta: effect on binding to p22phox and on NADPH oxidase activation. Biochemistry 2002 Jun 18;41(24):7743-50
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    Protein kinase C (PKC) isoforms translocate to Triton-insoluble fractions in stimulated human neutrophils: correlation of conventional PKC with activation of NADPH oxidase. Journal of immunology (Baltimore, Md. : 1950) 1999 Oct 15;163(8):4574-82
  51. Bokoch GM, Diebold BA
    Current molecular models for NADPH oxidase regulation by Rac GTPase. Blood 2002 Oct 15;100(8):2692-6
  52. Shalom-Barak T, Knaus UG
    A p21-activated kinase-controlled metabolic switch up-regulates phagocyte NADPH oxidase. The Journal of biological chemistry 2002 Oct 25;277(43):40659-65
  53. Carstanjen D, Yamauchi A, Koornneef A, Zang H, Filippi MD, Harris C, Towe J, Atkinson S, Zheng Y, Dinauer MC, Williams DA
    Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways. Journal of immunology (Baltimore, Md. : 1950) 2005 Apr 15;174(8):4613-20
  54. Martyn KD, Kim MJ, Quinn MT, Dinauer MC, Knaus UG
    p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils. Blood 2005 Dec 1;106(12):3962-9

  1. Karp CL, Flick LM, Yang R, Uddin J, Petasis NA
    Cystic fibrosis and lipoxins. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):263-70
  2. Karp CL, Flick LM, Park KW, Softic S, Greer TM, Keledjian R, Yang R, Uddin J, Guggino WB, Atabani SF, Belkaid Y, Xu Y, Whitsett JA, Accurso FJ, Wills-Karp M, Petasis NA
    Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nature immunology 2004 Apr;5(4):388-92
  3. Takai D, Nagase T, Shimizu T
    New therapeutic key for cystic fibrosis: a role for lipoxins. Nature immunology 2004 Apr;5(4):357-8
  4. Ito N, Yokomizo T, Sasaki T, Kurosu H, Penninger J, Kanaho Y, Katada T, Hanaoka K, Shimizu T
    Requirement of phosphatidylinositol 3-kinase activation and calcium influx for leukotriene B4-induced enzyme release. The Journal of biological chemistry 2002 Nov 22;277(47):44898-904
  5. Chmiel JF, Davis PB
    State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection? Respiratory research 2003;4:8
  6. Bonnans C, Levy BD
    Lipid mediators as agonists for the resolution of acute lung inflammation and injury. American journal of respiratory cell and molecular biology 2007 Feb;36(2):201-5
  7. Chiang N, Arita M, Serhan CN
    Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):163-77
  8. Serhan CN
    Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual review of immunology 2007;25:101-37
  9. Filep JG, Khreiss T, Jozsef L
    Lipoxins and aspirin-triggered lipoxins in neutrophil adhesion and signal transduction. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):257-62
  10. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN
    Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. The Journal of experimental medicine 1997 May 5;185(9):1693-704
  11. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T
    A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997 Jun 5;387(6633):620-4
  12. El Kebir D, Jozsef L, Khreiss T, Pan W, Petasis NA, Serhan CN, Filep JG
    Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation. Journal of immunology (Baltimore, Md. : 1950) 2007 Jul 1;179(1):616-22
  13. Serhan CN
    Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):141-62
  14. Gaudreau R, Le Gouill C, Metaoui S, Lemire S, Stankova J, Rola-Pleszczynski M
    Signalling through the leukotriene B4 receptor involves both alphai and alpha16, but not alphaq or alpha11 G-protein subunits. The Biochemical journal 1998 Oct 1;335 ( Pt 1):15-8
  15. Gaudreau R, Le Gouill C, Venne MH, Stankova J, Rola-Pleszczynski M
    Threonine 308 within a putative casein kinase 2 site of the cytoplasmic tail of leukotriene B(4) receptor (BLT1) is crucial for ligand-induced, G-protein-coupled receptor-specific kinase 6-mediated desensitization. The Journal of biological chemistry 2002 Aug 30;277(35):31567-76
  16. Niggli V
    Signaling to migration in neutrophils: importance of localized pathways. The international journal of biochemistry & cell biology 2003 Dec;35(12):1619-38
  17. Hou C, Kirchner T, Singer M, Matheis M, Argentieri D, Cavender D
    In vivo activity of a phospholipase C inhibitor, 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), in acute and chronic inflammatory reactions. The Journal of pharmacology and experimental therapeutics 2004 May;309(2):697-704
  18. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  19. Goldman DW, Chang FH, Gifford LA, Goetzl EJ, Bourne HR
    Pertussis toxin inhibition of chemotactic factor-induced calcium mobilization and function in human polymorphonuclear leukocytes. The Journal of experimental medicine 1985 Jul 1;162(1):145-56
  20. Andersson T, Schlegel W, Monod A, Krause KH, Stendahl O, Lew DP
    Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1,4,5-trisphosphate. A second messenger for Ca2+ mobilization. The Biochemical journal 1986 Dec 1;240(2):333-40
  21. Lew PD, Dayer JM, Wollheim CB, Pozzan T
    Effect of leukotriene B4, prostaglandin E2 and arachidonic acid on cytosolic-free calcium in human neutrophils. FEBS letters 1984 Jan 23;166(1):44-8
  22. Lee JS, Kim JH, Jang IH, Kim HS, Han JM, Kazlauskas A, Yagisawa H, Suh PG, Ryu SH
    Phosphatidylinositol (3,4,5)-trisphosphate specifically interacts with the phox homology domain of phospholipase D1 and stimulates its activity. Journal of cell science 2005 Oct 1;118(Pt 19):4405-13
  23. Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J
    Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. The Biochemical journal 1999 Feb 1;337 ( Pt 3):575-83
  24. Di Paolo G, De Camilli P
    Phosphoinositides in cell regulation and membrane dynamics. Nature 2006 Oct 12;443(7112):651-7
  25. Nakanishi H, Brewer KA, Exton JH
    Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. The Journal of biological chemistry 1993 Jan 5;268(1):13-6
  26. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR
    P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 2002 Mar 22;108(6):809-21
  27. Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC, Hawkins PT, Stephens LR
    Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. The Journal of biological chemistry 2005 Feb 11;280(6):4166-73
  28. Welch HC, Condliffe AM, Milne LJ, Ferguson GJ, Hill K, Webb LM, Okkenhaug K, Coadwell WJ, Andrews SR, Thelen M, Jones GE, Hawkins PT, Stephens LR
    P-Rex1 regulates neutrophil function. Current biology : CB 2005 Oct 25;15(20):1867-73
  29. Hill K, Welch HC
    Purification of P-Rex1 from neutrophils and nucleotide exchange assay. Methods in enzymology 2006;406:26-41
  30. Bokoch GM, Zhao T
    Regulation of the phagocyte NADPH oxidase by Rac GTPase. Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1533-48
  31. Jones SA, Wolf M, Qin S, Mackay CR, Baggiolini M
    Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. Proceedings of the National Academy of Sciences of the United States of America 1996 Jun 25;93(13):6682-6
  32. Asagoe K, Yamamoto K, Takahashi A, Suzuki K, Maeda A, Nohgawa M, Harakawa N, Takano K, Mukaida N, Matsushima K, Okuma M, Sasada M
    Down-regulation of CXCR2 expression on human polymorphonuclear leukocytes by TNF-alpha. Journal of immunology (Baltimore, Md. : 1950) 1998 May 1;160(9):4518-25
  33. Mukaida N
    Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. American journal of physiology. Lung cellular and molecular physiology 2003 Apr;284(4):L566-77
  34. Fukunaga K, Arita M, Takahashi M, Morris AJ, Pfeffer M, Levy BD
    Identification and functional characterization of a presqualene diphosphate phosphatase. The Journal of biological chemistry 2006 Apr 7;281(14):9490-7
  35. Levy BD, Fokin VV, Clark JM, Wakelam MJ, Petasis NA, Serhan CN
    Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A4. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999 May;13(8):903-11
  36. Levy BD, Serhan CN
    A novel polyisoprenyl phosphate signaling cascade in human neutrophils. Annals of the New York Academy of Sciences 2000 Apr;905:69-80
  37. Levy BD, Serhan CN
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