Inhibitory action of Lipoxins and Resolvin E1 on neutrophil
Deregulated neutrophilic inflammation and chronic infection lead to progressive
destruction of the airways in cystic fibrosis (CF). In normal tissues, the lipoxins and
resolvins are endogenous anti-inflammatory lipid mediators that are important as
regulators of neutrophilic inflammation , , . In CF, production of lipoxins is impaired , .
In response to infection or tissue injury, arachidonic acid produces proinflammatory
Leukotriene B4 that leads to neutrophil recruitment and
acute inflammation , , .
Lipoxins are bioactive eicosanoids derived from arachidonic acid. In contrast to
proinflammatory leukotrienes and prostaglandins, lipoxins (Lipoxin
A4 and 15-epi-LXA4) display potent
antiinflammatory actions, including attenuation of neutrophil respiratory burst and
transendothelial migration , .
Lipoxins mediate a transition from acute to chronic inflammation and promote
resolution , , . 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 , , .
Resolvin E1 is also a potent anti-inflammatory and
proresolving mediator derived from omega-3 eicosapentaenoic acid produced during the
resolution phase of inflammation. Resolvin E1 possesses a
unique structure and counter-regulatory actions that stop human neutrophil
transendothelial migration , , .
Leukotriene B4 and Lipoxins (Lipoxin
A4 and 15-epi-LXA4) interact with highly
specific and distinct G protein-coupled membrane receptors , ,  to evoke opposing leukocyte responses, including
Lipoxin A4 inhibition of Leukotriene
B4-initiated respiratory burst, chemotaxis, adhesion, and transmigration
Leukotriene B4 binds to the Leukotriene B4 receptor
(LTBR1) that via G-protein alpha-i family
and G-protein beta/gamma subunits activates
Phosphatidylinositol 3-kinase (PI3K reg class IB (p101) and
PI3K cat class IB (p110-gamma)) signaling , .
Resolvin E1 selective binding to
LTBR1 blocks its stimulation by Leukotriene
B4 and inhibits receptor signaling. Resolvin
E1/ LTBR1 interaction followed by
attenuation of neutrophil superoxide production and transendothelial migration leads to
the resolution of acute inflammation .
Lipoxin A4 and 15-epi-LXA4
interact with the Formyl peptide receptor-like 1 (FPRL1)
, , ,  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 presqualene diphosphate
phosphatase that converts Presqualene diphosphate to
Presqualene monophosphate . 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 , .
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 , , , , , .
Protein kinase C zeta (PKC-zeta) is activated downstream
of Phosphatidylinositol 3-kinase signaling , , .
PLD1 hydrolyzes membrane
Phosphatidylcholines to generate Phosphatidic
acid, a powerful activator of PKC-zeta, which
phosphorylates NADPH oxidase complex subunits , , , , .
Lipoxin A4 (or 15-epi-LXA4)/ (FPRL1) signaling leads to accumulation of
Presqualene diphosphate, and, thereby, blocks assembly of
NADPH oxidase , . Decreased Superoxide anion
(O(2)(-)) production is consistent with a shift in the
O(2)(-) / Nitric Oxide ratio,
resulting in decreased Peroxynitrite (ONOO(-)) formation.
Reductions in ONOO(-) formation are associated with
attenuation of nuclear accumulation of transcription factors Nuclear factor kappa-B
(NF-kB) and AP-1 (c-Jun/c-Fos),
which act in concert to induce Interleukin 8 (IL-8) gene
Lipoxin A4 and 15-epi-LXA4
signaling may protect NF-kappa-B inhibitor alpha (NFKBIA)
from nitration by ONOO(-) , thereby
preventing activation of NF-kB, or may attenuate
Mitogen-activated protein kinase kinase kinase 14
(NIK(MAP3K14))/ I-kappa-B kinase-alpha
(IKK-alpha)/ NF-kappa-B inhibitor
(I-kB)/ NF-kB pathway , .
Leukotriene B4 also induces neutrophil migration by
Reactive oxygen species-Extracellular signal-regulated kinases 1 and 2
(ERK1/2)-linked cascade . Superoxide
(O(2)(-)) production results in Hydrogen
peroxide formation , , .
ERK1/2 activated by Hydrogen peroxide
,  can modulate the actin/myosin
cytoskeleton remodeling necessary for cell motility , , , , and, possibly, can participate in
IL-8 is one of the key pro-inflammatory chemokines in the
airways of CF patients; therefore Lipoxin- and Resolvin-induced counter-regulation of
IL-8 expression is the critical pathway for 'stop-signaling'
to neutrophil accumulation and for resolving stage of acute inflammation , , , , , , , .
- 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
- Serhan CN
Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.
Annual review of immunology 2007;25:101-37
- Ariel A, Serhan CN
Resolvins and protectins in the termination program of acute inflammation.
Trends in immunology 2007 Apr;28(4):176-83
- 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
- Takai D, Nagase T, Shimizu T
New therapeutic key for cystic fibrosis: a role for lipoxins.
Nature immunology 2004 Apr;5(4):357-8
- 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
- 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
- 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
- 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
- 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
- Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN
Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation.
Journal of immunology (Baltimore, Md. : 1950) 2007 Mar 15;178(6):3912-7
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Levy BD, Serhan CN
Polyisoprenyl phosphates: natural antiinflammatory lipid signals.
Cellular and molecular life sciences : CMLS 2002 May;59(5):729-41
- 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
- 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
- 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
- Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR
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
- Frey RS, Gao X, Javaid K, Siddiqui SS, Rahman A, Malik AB
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
- Billah MM, Eckel S, Mullmann TJ, Egan RW, Siegel MI
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
- 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
- Limatola C, Barabino B, Nista A, Santoni A
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
- Dang PM, Fontayne A, Hakim J, El Benna J, Perianin A
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
- 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
- Zouki C, Jozsef L, Ouellet S, Paquette Y, Filep JG
Peroxynitrite mediates cytokine-induced IL-8 gene expression and production by human leukocytes.
Journal of leukocyte biology 2001 May;69(5):815-24
- Matata BM, Gali?anes M
Peroxynitrite is an essential component of cytokines production mechanism in human monocytes through modulation of nuclear factor-kappa B DNA binding activity.
The Journal of biological chemistry 2002 Jan 18;277(3):2330-5
- Je JH, Lee JY, Jung KJ, Sung B, Go EK, Yu BP, Chung HY
NF-kappaB activation mechanism of 4-hydroxyhexenal via NIK/IKK and p38 MAPK pathway.
FEBS letters 2004 May 21;566(1-3):183-9
- Woo CH, Yoo MH, You HJ, Cho SH, Mun YC, Seong CM, Kim JH
Transepithelial migration of neutrophils in response to leukotriene B4 is mediated by a reactive oxygen species-extracellular signal-regulated kinase-linked cascade.
Journal of immunology (Baltimore, Md. : 1950) 2003 Jun 15;170(12):6273-9
- Larfars G, Lantoine F, Devynck MA, Palmblad J, Gyllenhammar H
Activation of nitric oxide release and oxidative metabolism by leukotrienes B4, C4, and D4 in human polymorphonuclear leukocytes.
Blood 1999 Feb 15;93(4):1399-405
- Serezani CH, Aronoff DM, Jancar S, Peters-Golden M
Leukotriene B4 mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acid-stimulated neutrophils.
Journal of leukocyte biology 2005 Oct;78(4):976-84
- Bokoch GM, Zhao T
Regulation of the phagocyte NADPH oxidase by Rac GTPase.
Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1533-48
- Lee K, Esselman WJ
Inhibition of PTPs by H(2)O(2) regulates the activation of distinct MAPK pathways.
Free radical biology & medicine 2002 Oct 15;33(8):1121-32
- Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA
Regulation of cell motility by mitogen-activated protein kinase.
The Journal of cell biology 1997 Apr 21;137(2):481-92
- Cheresh DA, Leng J, Klemke RL
Regulation of cell contraction and membrane ruffling by distinct signals in migratory cells.
The Journal of cell biology 1999 Sep 6;146(5):1107-16
- Pfitzer G
Invited review: regulation of myosin phosphorylation in smooth muscle.
Journal of applied physiology (Bethesda, Md. : 1985) 2001 Jul;91(1):497-503
- Xiao D, Longo LD, Zhang L
Alpha1-adrenoceptor-mediated phosphorylation of MYPT-1 and CPI-17 in the uterine artery: role of ERK/PKC.
American journal of physiology. Heart and circulatory physiology 2005 Jun;288(6):H2828-35
- Brennan S, Cooper D, Sly PD
Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin.
Thorax 2001 Jan;56(1):62-4
- Tabary O, Corvol H, Boncoeur E, Chadelat K, Fitting C, Cavaillon JM, Clement A, Jacquot J
Adherence of airway neutrophils and inflammatory response are increased in CF airway epithelial cell-neutrophil interactions.
American journal of physiology. Lung cellular and molecular physiology 2006 Mar;290(3):L588-96
- Boncoeur E, Criq VS, Bonvin E, Roque T, Henrion-Caude A, Gruenert DC, Clement A, Jacquot J, Tabary O
Oxidative stress induces extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase in cystic fibrosis lung epithelial cells: Potential mechanism for excessive IL-8 expression.
The international journal of biochemistry & cell biology 2008;40(3):432-46
- Nichols D, Chmiel J, Berger M
Chronic inflammation in the cystic fibrosis lung: alterations in inter- and intracellular signaling.
Clinical reviews in allergy & immunology 2008 Apr;34(2):146-62