Published online before print May 21, 2008
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of Montréal, Montréal, Quebec, Canada
1 Correspondence: Research Center, Maisonneuve-Rosemont Hospital, 5415 Boulevard de l’Assomption, Montréal, QC, Canada, H1T 2M4. E-mail: janos.g.filep{at}umontreal.ca
ABSTRACT
Neutrophils have a central role in innate immunity, and their programmed cell death and removal are critical to the optimal expression as well as to efficient resolution of inflammation. Human neutrophils express the pleiotropic receptor formyl peptide receptor-like 1/lipoxin A4 (LXA4) receptor that binds a variety of ligands, including the acute-phase reactant serum amyloid A (SAA), the anti-inflammatory lipids LXA4 and aspirin-triggered 15-epi-LXA4 (ATL), and the glucocorticoid-inducible protein annexin 1. In addition to regulation of neutrophil activation and recruitment, these ligands have a profound influence on neutrophil survival and apoptosis with contrasting actions, mediating aggravation or resolution of the inflammatory response. Thus, annexin 1 accelerates, whereas SAA rescues human neutrophils from constitutive apoptosis by preventing mitochondrial dysfunction and subsequent activation of caspase-3. Furthermore, ATL overcomes the antiapoptosis signal from SAA and redirects neutrophils to caspase-mediated cell death. We review recent developments about the molecular basis of these actions and suggest a novel mechanism by which aspirin promotes resolution of acute inflammation and tissue injury.
Key Words: acute-phase reactants • lipid mediators
INTRODUCTION
Neutrophils play a central role in innate immunity. They are rapidly recruited to sites of infection and injury. Their many defense mechanisms that digest and destroy invading pathogens are also capable of inflicting damage to surrounding tissues [1
, 2
]. Thus, it is vital that neutrophil functions are regulated tightly. Neutrophil trafficking into inflamed tissues is intimately linked to prolonged survival. Mature neutrophils have the shortest half-life (
7 h) among leukocytes and die rapidly via apoptosis [3
4
5
]. This constitutively expressed cell death program renders neutrophils unresponsive to chemoattractants and allows their recognition and removal from inflamed areas by scavenger macrophages [3
] with minimal damage to the surrounding tissue, thereby facilitating the resolution of inflammation [6
, 7
]. Neutrophil survival and apoptosis are profoundly influenced by signals from the inflammatory microenvironment [8
]. Inflammatory mediators, such as LPS or proinflammatory cytokines, rescue neutrophils from apoptosis, whereas the presence of proapoptotic stimuli such TNF-
and Fas ligand markedly shortens the neutrophil lifespan [7
]. If neutrophil apoptosis or macrophage phagocytosis is impaired, chronic inflammation may ensue [7
, 8
]. Indeed, markedly suppressed neutrophil apoptosis has been detected in patients with inflammatory diseases, including acute respiratory distress syndrome [9
], sepsis [10
], and acute coronary artery disease [11
]. The regulation of neutrophil apoptosis during the acute phase of inflammation is less well defined, yet it is critical to the optimal expression and resolution of inflammation. Recent studies indicate that the acute-phase protein serum amyloid A (SAA) prolongs neutrophil longevity by suppressing constitutive apoptosis. Moreover, recent findings suggest that SAA exerts its biological actions predominantly through binding to the pleiotropic receptor formyl-peptide receptor-like 1 (FPRL1) [12
, 13
], which also binds the anti-inflammatory lipid lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4 (ATL) and annexin 1 [14
].
Here, we describe these recent findings and discuss how interactions between various FPRL1/LXA4 receptor (ALX) ligands may orchestrate inflammatory responses as well as resolution of inflammation through modulation of neutrophil apoptosis.
LIGANDS FOR THE FPRL1/ALX
The three formyl-peptide-related receptors, FPR, FPRL1, and FPRL2, share significant sequence homology amongst themselves but have different pharmacological properties (reviewed in ref. [14 ]). FPR and FPRL1 bind fMLP with high- and low-affinity, respectively. A systematic approach of screening orphan receptors that are induced during myeloid cell differentiation led to identification of LXA4 and ATL as high-affinity ligands for FPRL1/ALX [14 ], which is a pleiotropic receptor that also binds other structurally unrelated peptide/protein ligands in vitro, including SAA [12 , 13 ], glucocorticoid-induced annexin 1 [15 ], amyloid β (Aβ42) [16 ], MHC-binding peptide [14 ], a urokinase-type plasminogen activator receptor fragment [17 ], a mitochondrion peptide fragment derived from NADH dehydrogenase subunit 1 [18 ], bacteria-derived peptide Hp2-20 (from Helicobacter pylori) [14 ], neurotoxic prion peptide fragments (PrP106–126) [19 ], HIV-1 envelop protein domains [20 ], and synthetic peptides [14 ]. Some of these protein/peptides interact with FPRL1/ALX in the nanomolar range. For instance, the Kd value for SAA is 45 nM and for MHC-binding peptide is 1 nM compared with the Kd value of 1.7 nM for LXA4 and ATL [14 ]. It is noteworthy that FPRL1/ALX ligands do not share significant sequence homology with one another or with fMLP, and their functional role(s) in human pathology remain to be addressed.
MODULATION OF LEUKOCYTE ACTIVATION BY SAA
SAA is a 12-kDa protein produced predominantly in the liver [21
]. SAA mRNA expression has also been detected in human atherosclerotic lesions, cultured carotid artery endothelial and smooth muscle cells [22
], and rheumatoid arthritis (RA) synovial tissues [23
, 24
]. The proinflammatory cytokines IL-1β, TNF-, and IL-6 are potent inducers of SAA expression by hepatocytes and to various degrees, by macrophages and synoviocytes [25
, 26
]. In the blood, SAA is almost exclusively associated with high-density lipoproteins (HDLs) at lower concentrations, but it dissociates from HDLs at higher concentrations [27
, 28
]. In healthy subjects, serum concentration of SAA is <1 µg/ml or 80 nM; it can increase as much as 1000-fold within 24 h in response to infection or tissue damage [29
]. Elevated plasma levels of SAA have been noted in a variety of pathological conditions [26
, 29
] and portend a worse prognosis in RA [30
] and unstable angina [31
, 32
], conditions that are also associated with extensive neutrophil activation [2
, 33
]. Free SAA was also detected in inflamed tissues [22
, 23
], suggesting a potential role for SAA in chronic inflammation.
SAA has a unique profile of biological activities [21
, 29
]. The precise role of SAA as a modulator of inflammation remains elusive, as it possesses beneficial and harmful actions. For instance, SAA facilitates reverse transport of cholesterol [34
], opsonizes Gram-negative bacteria [35
], and enhances phagocytosis [36
], but it is also a precursor of amyloid A, the deposit of which causes amyloidosis [26
]. SAA stimulates release of TNF-, IL-1β, and IL-8 from neutrophils and monocytes [13
, 37
]. The induction of IL-8 secretion involves transcription and translation, correlates with NF-
B activation, and requires calcium mobilization and activation of ERK1/2 and p38 MAPK [13
]. SAA also evokes production of matrix metalloproteinases [38
], IL-1R antagonist, and soluble TNFR- type II [39
].
A number of studies suggest a link between SAA and leukocyte trafficking. I.v. injection of SAA into mice increases the number of circulating neutrophils through stimulating G-CSF secretion by monocytes/macrophages [40 ]. SAA is chemotactic to neutrophils, monocytes, and T lymphocytes [12 , 41 ], regulates L-selectin and CD11b expression on leukocytes [41 ], and promotes neutrophil adhesion to endothelial cells [42 ].
The chemotactic- and cytokine-releasing actions of SAA are mediated through the G-protein-coupled FPRL1/ALX [12 13 14 ]. However, certain actions of SAA may be mediated through receptors distinct from FPRL1/ALX. Thus, desensitization of FPRL1/ALX and the FPRL1-specific antagonist WRWWWW (WRW4) does not block SAA-induced NADPH oxidase activation in human neutrophils [42 ]. The SAA action can be blocked by pertussis toxin, indicating that the receptor involved is a G-protein-coupled receptor. Of note, neutrophils from gp91phox-deficient patients are hyper-responsive to SAA, despite lack of NADPH oxidase activity [43 ]. The receptor mediating this action also remains to be identified. Furthermore, a recent study reported that SAA-stimulated G-CSF production is markedly attenuated in TLR-2-deficient mice, raising the intriguing possibility that SAA may also bind to TLR-2 [40 ].
LXA4 AND ATL
Lipoxins are generated locally at sites of inflammation by transcellular biosynthesis, involving interaction of neutrophils with platelets or resident tissue cells, such as epithelial cells [44 ]. In the third pathway, acetylation at Ser530 by aspirin [45 ] or S-nitrosylation at Cys526 by atorvastatin [46 ] redirects the catalytic activity of cyclooxygenase 2 to catalyze the conversion of arachidonate to 15R-5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid that can be converted by neutrophils and other cells to ATL. In a murine air-pouch model of inflammation, accumulation of PGE2 induces a switch in lipid mediator synthesis from a predominantly 5-lipoxygenase activity to a 15-lipoxygenase activity generating LXA4, parallel with resolution of inflammation [47 ]. ATL formation has been detected in an aspirin-dependent manner in various murine models of inflammation (reviewed in ref. [14 ]) as well as in aspirin-tolerant asthmatics [48 ]. Aspirin at clinically relevant doses increases plasma ATL levels and blocks thromboxane formation in healthy volunteers [49 ].
LXA4 and ATL have diverse actions on individual leukocytes. Lipoxins stimulate activation and recruitment of monocytes/macrophages, and they inhibit neutrophil chemotaxis, adherence, and transmigration across the vascular endothelium and epithelium (for review, see refs. [14
, 50
]), down-regulate CD11b/CD18 expression [51
, 52
], block superoxide generation [53
], attenuate NF-B and AP-1 activation [54
], and suppress IL-8 secretion [54
]. Lipoxins also inhibit activation of eosinophils, T lymphocytes, and NK cells [14
]. Consistently, LXA4/ATL were reported to inhibit neutrophil recruitment and disease severity in a number of inflammation models, including dermal inflammation, ischemia/reperfusion injury, peritonitis, colitis, cystic fibrosis, asthma, and glomerulonephritis (reviewed in refs. [14
, 50
]).
Most of the anti-inflammatory actions of LXA4/ATL are mediated through activation of FPRL1/ALX [14
], leading to generation of cell type-specific, anti-inflammatory signals. For instance, LXA4 evokes Ca2+ mobilization in monocytes [55
]. In neutrophils, LXA4/ATL attenuates leukotriene B4 (LTB4) and fMLP-induced Ca2+ mobilization [56
], reverses LTB4-evoked polyisoprenyl phosphate remodeling [53
], and reduces peroxynitrite-mediated activation of NF-B and AP-1 and IL-8 gene transcription [54
]. ATL inhibits leukocyte trafficking in a NO-dependent manner on IL-1β-stimulated mouse mesentery [57
]. LXA4/ATL triggers expression of suppressor of cytokine signaling (SOCS)-2 in dendritic cells [58
] and attenuates TNF- release from human T cells by attenuating ERK activation [59
].
Recent data demonstrate convergence of two endogenous anti-inflammation mechanisms: ATL and annexin 1 at FPRL1/ALX [15 , 60 ]. Like ATL, annexin 1 and the annexin 1-mimetic peptide Ac2-26 limit neutrophil infiltration and reduce production of inflammatory mediators in murine air pouches, and the protective actions of ATL and peptide Ac2-26 are additive [15 ]. ATL and peptide Ac2-26 induce detachment of adherent leukocytes in the mouse models of mesenteric ischemia-reperfusion [61 ] and myocardial infarction [62 ]. LXA4 and peptide Ac2-26 facilitate nonphlogistic phagocytosis of apoptotic neutrophils by macrophages [63 , 64 ]. These findings likely indicate existence of functional redundancies in endogenous anti-inflammation circuits during resolution of inflammation.
It is noteworthy that LXA4/ATL also competes with LTD4 at cysteinyl leukotriene receptors in neutrophils (reviewed in ref. [14 ]) and may also bind to a nuclear receptor, the aryl hydrocarbon receptor (AhR) [65 ]. Activation of AhR contributes to LXA4/ATL induction of SOCS-2 in mice [58 ] and triggers transcription of genes that are implicated in degradation of lipoxins [65 ].
SAA PROLONGS NEUTROPHIL SURVIVAL BY DELAYING APOPTOSIS
The default state of mature neutrophils is apoptosis. The impact of pathogens and inflammatory mediators on neutrophil survival has long been known [4 , 5 ]; it is only recently that the effects of the typical acute-phase reactants, C-reactive protein, and SAA have been studied.
Consistent with the commitment of neutrophils to apoptosis, recombinant human SAA at clinically relevant concentrations delays, rather than blocks, intrinsic apoptosis, resulting in prolonged neutrophil survival as assessed in vitro [66 ]. Furthermore, recombinant SAA or SAA purified from plasma of RA patients suppresses anti-Fas antibody-induced neutrophil apoptosis [67 ]. These observations also indicate that modest increases in SAA level over baseline value are sufficient to generate an antiapoptosis signal for neutrophils. The SAA actions are not a result of endotoxin contamination, as LPS at 2 ng/ml (the highest level detected in recombinant SAA preparations) does not suppress neutrophil apoptosis [66 ], and polymixin B does not affect the SAA inhibition [67 ]. The degree of the SAA inhibition of constitutive apoptosis is comparable with those of LPS [4 ] and structurally modified C-reactive protein [68 ].
The FPR antagonist N-t-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) was reported to effectively inhibit the SAA actions. Boc2 is a potent antagonist of binding of formyl peptides to neutrophils, and it also blocks binding of annexin-1 to FPRL1/ALX [69 ]. SAA and annexin 1 may share recognition sites on neutrophils [15 ]. As the FPR does not bind SAA [12 , 13 ], Boc2 most likely inhibited SAA binding to FPRL1/ALX, although we cannot categorically exclude SAA binding to other unrelated receptors. Indeed, a recent paper reported that the FPRL1 antagonist WRW4 [70 ] and the putative inhibitor of FPRL1-mediated signal transduction cell-permeable 10 aa peptide (PBP10) do not reverse SAA suppression of neutrophil apoptosis [67 ]. Comparison of these apparently discordant results is complicated by the fact that the biological profile of WRW4 and PBP10 has not fully been explored and that the latter study was performed on neutrophils, which were stored for an unspecified time on melting ice.
Neutrophil apoptosis is controlled by a complex network of signaling pathways, including the ERK, Akt, and p38 MAPK pathways [4
, 68
, 71
, 72
]. Two lines of evidence indicate that SAA also uses these pathways. SAA evokes a rapid phosphorylation of ERK1/2 and Akt in human neutrophils, and pharmacological blockade of MAPK/ERK or PI-3K effectively, although never completely, blocks the apoptosis-delaying action of SAA [66
]. As SAA-stimulated ERK activation is also required for the induction of IL-8 secretion [13
], ERK may link neutrophil activation to suppression of apoptosis by SAA. Transient activation of PI-3K without ERK activation may not be sufficient to delay apoptosis [72
]. Simultaneous ERK and Akt blockade does not produce additive inhibition [66
], indicating that ERK1/2 and Akt work in concert to delay neutrophil apoptosis. These pathways converge on Bad, a proapoptotic member of the Bcl-2 family. SAA induces phosphorylation of Bad at Ser112 and Ser136 through activation of ERK and Akt, respectively [66
]. Phosphorylated Bad then dissociates from the antiapoptotic Bcl-2 homologue Mcl-1 expressed in neutrophils, allowing expression of the antiapoptotic actions of Mcl-1. These include prevention of mitochondrial membrane potential transition and consequently, loss in the mitochondrial transmembrane potential (
m), which occurs in cells irreversibly committed to programmed cell death [73
, 74
]. Mature neutrophils do contain an unexpectedly large number of mitochondria [75
] that may have a role restricted to apoptosis [76
]. Indeed, development of apoptotic morphology is preceded by decreases in m and subsequent release of cytochrome c from the mitochondria into the cytoplasm and activation of caspase-3 in human neutrophils undergoing constitutive apoptosis [71
, 76
, 77
]. These events are partially prevented by SAA, parallel with suppression of neutrophil apoptosis [66
]. Furthermore, the pan-caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone and SAA do not produce additive inhibition of neutrophil apoptosis, confirming the importance of SAA reduction of caspase-3 activation. Thus, major mechanisms by which SAA rescues neutrophils from constitutive apoptosis are ERK- and PI-3K-dependent prevention of mitochondrial dysfunction and repression of caspase-3 activity (Fig. 1
).
 View larger version (25K): [in a new window] |
Figure 1. Mechanisms for the apoptosis-delaying action of SAA in human neutrophils and its reversal by LXA4 and ATL. SAA binds to the protein-binding domain of the FPRL1/ALX and induces phosphorylation of the proapoptotic protein Bad through activation of the PI-3K/Akt and MEK/ERK pathway. Phosphorylated Bad then dissociates from Mcl-1, thus allowing expression of Mcl-1 antiapoptotic activities, including prevention of the collapse of m, cytochrome c release, and activation of caspase-3, characteristic features of neutrophils undergoing constitutive apoptosis. LXA4/ATL binds to the lipid-binding domain of FPRL1/ALX and through yet-unidentified mechanisms, over-rides the SAA survival signal and redirects neutrophils to apoptosis.
|
Recently, the nucleotide receptor P2X7 has been implicated in mediating SAA suppression of neutrophil apoptosis. This notion is based on the observations that periodate-oxidized ATP and Comassie brilliant blue reverse the SAA action [67 ]. One should recall that human neutrophils do express P2X7 at a low level [80 ], and oxidized ATP effectively dampens inflammation in P2X7-deficient mice [81 ], raising questions about the involvement of this receptor.
Unlike SAA, another FPRL1/ALX ligand annexin 1 was reported to accelerate neutrophil apoptosis [82 ]. This was unexpected in view of the antiapoptotic actions of glucocorticoids [83 ]. However, extravasated neutrophils contribute to annexin 1 expression within inflamed tissue, and this occurs in a glucocorticoid-independent manner [84 ]. Studies with chimeric annexin 1 proteins point toward a role for the N-terminal region of annexin 1 in promoting neutrophil apoptosis [82 ], although the contribution of another sequence (corresponding to residues 246–258, also known as antiflammin-2) in annexin 1, which mimics the effect of the parent molecule on neutrophil adhesion [85 ], remains to be investigated. The proapoptotic action of annexin 1 requires entry of extracellular calcium and activation of caspase-3 [86 ]. Jurkat T cell apoptosis is associated with Ca2+ and caspase-dependent externalization of annexin 1 [87 ], which in turn promotes clustering of phosphatidylserine receptors, thereby ensuring efficient engulfment of the apoptotic cells [86 ]. It is not known whether glucocorticoid promotion of phagocytosis of apoptotic neutrophils [88 ] involves externalization of annexin 1. Regardless of the precise molecular mechanisms involved, these observations suggest that activation of FPRL1/ALX may result in potent pro- or anti-inflammatory responses in a ligand-specific manner.
ATL OVER-RIDES SAA SUPPRESSION OF NEUTROPHIL APOPTOSIS
Although most studies focused on LXA4/ATL suppression of neutrophil activation, adherence, and recruitment as major anti-inflammatory, pro-resolution activities of these lipids [14
, 89
, 90
], a few studies investigated their impact on neutrophil apoptosis. Culture of neutrophils with LXA4, ATL, or their metabolically stable synthetic analogs, at nanomolar-to-low micromolar concentrations, fails to produce detectable changes in development of apoptosis [54
, 63
, 66
] and does not modify the antiapoptosis action of LPS [54
]. The inability of ATL to evoke activation of ERK and Akt [66
] may explain the lack of effect on neutrophil survival and apoptosis. At high micromolar concentrations, LXA4 was found to stimulate fibroblast apoptosis [91
], suggesting cell-specific lipoxin actions. LXA4 and ATL facilitate phagocytosis of apoptotic neutrophils in vitro and in vivo rather than interfering directly with the neutrophil apoptotic machinery [63
, 92
]. More recently, we have reported that ATL over-rides a powerful antiapoptosis signal from SAA and redirects neutrophils to apoptosis [66
]. Indeed, pretreatment of neutrophils with ATL results in a marked attenuation of SAA prevention of m collapse and over-rides SAA suppression of apoptosis, further supporting their pro-resolution role. ATL markedly reduces SAA-induced ERK1/2 and Akt activation and consequently, phosphorylation of Bad at Ser112 and Ser136. ATL also produces a small inhibition of p38 MAPK phosphorylation by SAA [66
]. Interestingly, the apoptosis-promoting actions of ATL are detectable, albeit to a lesser degree, even when SAA-activated neutrophils were treated with ATL 60 min or 4 h post-SAA, indicating a therapeutic potential for this lipid [66
].
As expected, higher concentrations of ATL and its metabolically stable analogs (EC50 values approximately 0.5 µM) are required in the presence of human plasma to block neutrophil responses to SAA than in other isolated cells [13 , 66 ]. This might reflect interactions of lipoxins with serum components such as albumin. Nevertheless, it is impressive that these lipophilic compounds overcome interactions with plasma components to specifically regulate neutrophils. It is worth noting that ATL redirection of SAA-treated neutrophils to apoptosis resembles that of the anti-tumor drugs, cyclin-dependent kinase inhibitors [93 ].
The molecular basis for how FPRL1/ALX differently responds to various ligands remains enigmatic. Although ATL stimulates limited phosphorylation of p38 MAPK, this is insufficient to affect neutrophil apoptosis [66 ]. It is unlikely that ATL attenuation of SAA-induced activation of ERK and Akt pathways is a result of inhibition by ATL of SAA binding to FPRL1/ALX, as these ligands bind to distinct pockets on the receptor [18 ]. Indeed, an antibody against the N-terminal domain of this receptor blocks SAA but not LXA4 binding [13 ]. Whether binding to such pockets leads to different conformational changes in the receptor remains to be investigated. It is possible that ATL may generate a yet-unidentified, negative signal that blocks ERK and Akt. This possibility is supported by the observations that LXA4/ATL attenuates peroxynitrite signaling [54 ] via the regulation of presqualane diphosphate accumulation in human neutrophils [53 ]. Consistent with the observations in human neutrophils [66 ], LXA4/ATL inhibition of PI-3K was also noted in renal mesangial cells [94 , 95 ] and human lung fibroblasts [96 ], where they antagonize cell proliferation. In mesangial cells, LXA4 stimulates phosphorylation of ERK and p38 MAPK [94 ]. However, these results are not easily comparable, as neutrophils are terminally differentiated cells where MAPK kinases play different roles than in mesangial cells and fibroblasts.
CONCLUSIONS
In the past years, the molecular mechanisms underlining the removal of neutrophils are emerging. As illustrated above, activation of FPRL1/ALX likely triggers important pathways that among others are involved in orchestration of neutrophil activation, apoptosis, and thus, longevity (Fig. 2 ). This is an emerging field of research with a plethora of open questions. We have reviewed the current results about how activation of FPRL1/ALX by SAA, annexin 1, and LXA4/ATL may generate intracellular signals that facilitate, suppress, or reverse the suppression of neutrophil apoptosis. Although these observations bear directly on the mechanism for amplification and/or resolution of the inflammatory response, an important issue that remains open is the identification of the molecular mechanisms responsible for such diverse actions. Likewise, additional studies are required to identify receptors other than FPRL1/ALX that may mediate SAA actions. These issues notwithstanding, the results discussed here are in line with an emerging view of SAA displaying potent, proinflammatory activities that may contribute to prolongation and aggravation of the inflammatory response. Furthermore, the observation that ATL and its metabolically stable analogs are potent inhibitors of SAA suppression of neutrophil apoptosis is an important addition to the anti-inflammatory, pro-resolution profile of these compounds [14 , 90 ] and demonstrates a hitherto unrecognized potential for treatment of inflammatory diseases associated with enhanced SAA formation.
 View larger version (24K): [in a new window] |
Figure 2. Model of regulation of neutrophil activation and apoptosis via the FPRL1/ALX, which recognizes a variety of ligands, inducing opposing biological responses. SAA suppresses intrinsic apoptosis and activates neutrophils, thereby contributing to the inflammatory response. By contrast, the glucocorticoid-inducible protein annexin 1 and LXA4 and ATL act in concert to inhibit neutrophil trafficking and activation. Annexin 1 also accelerates the neutrophil death program. LXA4 and ATL have no effect on neutrophil apoptosis/survival but effectively over-ride the antiapoptosis signal from SAA and redirect neutrophils to apoptosis, thereby shortening their lifespan, consistent with the resolution of inflammation.
|
ACKNOWLEDGEMENTS
This work was supported by Grant MOP-64283 (to J. G. F.) and Doctoral Research Award (to L. J.) from the Canadian Institutes of Health Research. The authors have no financial conflict of interest.
Received November 18, 2007; revised April 14, 2008; accepted April 16, 2008.
REFERENCES
, interleukin-1β, and interleukin-8 by human blood neutrophil Biochem. Biophys. Res. Commun. 268,405-408[CrossRef][Medline]B and AP-1 activation, and IL-8 gene expression in human leukocytes Proc. Natl. Acad. Sci. USA 99,13266-13271 secretion from human T cells J. Immunol. 170,6266-6272This article has been cited by other articles:
 |
|
 |
|
  L. N. Kirpotina, A. I. Khlebnikov, I. A. Schepetkin, R. D. Ye, M.-J. Rabiet, M. A. Jutila, and M. T. Quinn Identification of Novel Small-Molecule Agonists for Human Formyl Peptide Receptors and Pharmacophore Models of Their Recognition Mol. Pharmacol., February 1, 2010; 77(2): 159 - 170. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
