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Formylpeptide Receptor N Antagonist at The The Endogenous Opioid Spinorphin Blocks fMet-Leu-Phe-Induced Neutrophil Chemotaxis by Acting as a Specific Antagonist at the N-Formylpeptide Receptor This information is current as Subtype FPR of September 27, 2021. Thomas S. Liang, Ji-Liang Gao, Omid Fatemi, Mark Lavigne, Thomas L. Leto and Philip M. Murphy J Immunol 2001; 167:6609-6614; ; doi: 10.4049/jimmunol.167.11.6609 Downloaded from http://www.jimmunol.org/content/167/11/6609 References This article cites 48 articles, 13 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/167/11/6609.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Endogenous Opioid Spinorphin Blocks fMet-Leu-Phe-Induced Neutrophil Chemotaxis by Acting as a Specific Antagonist at the N-Formylpeptide Receptor Subtype FPR Thomas S. Liang, Ji-Liang Gao, Omid Fatemi, Mark Lavigne, Thomas L. Leto, and Philip M. Murphy1 Spinorphin is an endogenous heptapeptide (leucylvalylvalyltyrosylprolyltryptophylthreonine), first isolated from bovine spinal cord, whose sequence matches a conserved region of ␤-hemoglobin. Also referred to as LVV-hemorphin-4 and a member of the nonclassical opioid hemorphin family, spinorphin inhibits enkephalin-degrading enzymes and is analgesic. Recently, spinorphin was reported to block neutrophil activation induced by the chemotactic N-formylpeptide N-formylmethionylleucylphenylalanine (fMLF), suggesting a potential role as an endogenous negative regulator of inflammation. Here we use both gain- and loss-of- Downloaded from function genetic tests to identify the specific mechanism of spinorphin action on neutrophils. Spinorphin induced calcium flux in normal mouse neutrophils, but was inactive in neutrophils from mice genetically deficient in the fMLF receptor subtype FPR (N-formylpeptide receptor). Consistent with this, spinorphin induced calcium flux in human embryonic kidney 293 cells trans- fected with mouse FPR, but had no effect on cells expressing the closely related fMLF receptor subtype FPR2. Despite acting as a calcium-mobilizing agonist at FPR, spinorphin was a weak chemotactic agonist and effectively blocked neutrophil chemotaxis induced by fMLF at concentrations selective for FPR. Spinorphin did not affect mouse neutrophil chemotaxis induced by con- http://www.jimmunol.org/ centrations of fMLF that selectively activate FPR2. Thus, spinorphin blocks fMLF-induced neutrophil chemotaxis by acting as a specific antagonist at the fMLF receptor subtype FPR. The Journal of Immunology, 2001, 167: 6609–6614. he generation of opioid peptides from endogenous pro- peptidase (18). Spinorphin has been identified in human cerebro- teins has been characterized in milk protein, mitochon- spinal fluid and bovine spinal cord (10, 18). Concentrations in vivo T drial cytochrome b, and hemoglobin (1–3). Hemorphins are not known, but high levels (115–300 nM) of the related he- are nonclassical opioid peptides found in human pituitary gland, morphin LVV-hemorphin-7 have been measured in cerebrospinal cerebrospinal fluid, adrenal gland, blood, and bronchoalveolar la- fluid from a patient with cerebrovascular bleeding (9). Spinorphin by guest on September 27, 2021 vage fluid as well as bovine brain that have amino acid sequences has been shown to have analgesic activity for morphine-resistant identical with a conserved region of the ␤-chain of bovine and pain pathways (19). human hemoglobin (4–10). Peritoneal macrophages (11) and pro- Expression of the spinorphin targets NEP and aminopeptidase N teolytic enzymes such as aspartic endopeptidase (12) and cathepsin (CD13) on blood phagocytes (20–24) has suggested a potential D (13) have been implicated in hemorphin processing and produc- role for spinorphin in modulating inflammatory responses. NEP tion. Hemorphins have been reported to function as agonists at degrades and inactivates the potent phagocyte chemoattractant AT4 angiotensin receptors in brain and as antagonists at enkeph- fMLF (25), suggesting that spinorphin might act to potentiate re- alinases and angiotensin-converting enzyme (14–17), suggesting sponses to this peptide. In fact, the opposite is the case; spinorphin potential modulatory roles in memory, pain, and blood pressure inhibits fMLF-induced calcium flux, chemotaxis, exocytosis, and control. superoxide production in human neutrophils (26). The mechanism Spinorphin, or LVV-hemorphin-4, has the amino acid sequence appears to involve competition for fMLF binding to surface re- leucyl-valyl-valyl-tyrosyl-prolyl-tryptophyl-threonine, which matches ceptors. Spinorphin has also been shown to block carrageenan- positions 32–38 of human ␤-hemoglobin (5). Like other hemor- induced polymorphonuclear neutrophil accumulation in mouse air phins, spinorphin is an angiotensin-converting enzyme antagonist, pouches (27). and inhibits enkephalin-degrading enzymes such as neutral endo- Here we address the molecular basis of spinorphin action by peptidase (NEP2/CD10), aminopeptidase, and dipeptidyl amino- testing its specificity for known fMLF receptors. Two human neu- trophil fMLF receptor subtypes have been cloned, N-formylpep- Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, tide receptor (FPR) and FPR-like 1 receptor (FPRL1R) (28–32). National Institutes of Health, Bethesda, MD 20892 These receptors are members of the G protein-coupled receptor Received for publication December 8, 2000. Accepted for publication September superfamily and have 69% amino acid identity. Compared with 24, 2001. FPR, FPRL1R binds fMLF with lower affinity and has additional The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance agonists, including lipoxin A4, and serum amyloid A (33, 34). In with 18 U.S.C. Section 1734 solely to indicate this fact. the mouse the FPR homologue has been clearly identified (35), but 1 Address correspondence and reprint requests to Dr. Philip M. Murphy, National two other related receptors have been cloned that are equally ho- Institutes of Health, Building 10, Room 11N113, Bethesda, MD 20892. E-mail ad- mologous to human FPRL1R (36). To date one has been charac- dress: [email protected] terized as a lipoxin A4 receptor and is known as LXA4R (37), 2 Abbreviations used in this paper: NEP, neutral endopeptidase; fMLF, N-formyl- methionyl-leucyl-phenylalanine; FPR, N-formylpeptide receptor; FPRL1R, FPR-like whereas the other, known as FPR2, is a functional receptor for 1 receptor; HEK, human embryonic kidney. fMLF (low affinity compared with mouse FPR) and serum amyloid Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 6610 SPINORPHIN ANTAGONISM OF N-FORMYLPEPTIDE RECEPTORS A (38, 39). Here we use gene transfected cell lines and FPR knock- out mice to prove that spinorphin blocks fMLF-induced chemo- taxis of neutrophils by specifically antagonizing FPR. Materials and Methods Peptides fMLF was purchased from Sigma (St. Louis, MO). Spinorphin was syn- thesized by the Peptide Synthesis and Analysis Unit, Research Technolo- gies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD). HPLC analysis indicated that the pep- tide was 93% pure. Both fMLF and spinorphin were dissolved in DMSO, and 10 mM stocks were kept at Ϫ20°C until use. Mouse leukocyte purification FIGURE 1. Spinorphin is a functional ligand for the fMLF receptor subtype FPR, but not for the related receptor FPR2. Calcium mobilization Development of an FPR knockout mouse has been reported previously was measured as relative cell fluorescence in HEK 293 cells transfected ϩ/Ϫ ϫ ϩ/Ϫ (40). Mice used in this study were littermates from FPR FPR with mouse FPR and mouse FPR2. The arrows indicate test molecules, matings of an F backcross of FPRϩ/Ϫ 129/Sv with wild-type C57BL/6 1 concentrations, and time of addition for each tracing. Each tracing corre- mice. Leukocytes were harvested from the peritoneal cavity after thiogly- colate irritation, as described previously (40). Cells obtained after 3 h were sponds to the receptor indicated to the left of the row in which it is found. Ͼ90% neutrophils, as determined by the morphologic appearance of Diff- Data are from a single representative experiment repeated at least three Quick-stained preparations. times. Downloaded from Cell lines Human embryonic kidney (HEK) 293 cell lines expressing mouse FPR and quential stimulation experiments, again monitoring calcium flux. mouse FPR2 have been previously described (37). Cells were cultured in A saturating concentration of spinorphin added first (500 ␮M) DMEM plus 10% FBS and 1 mg/ml G418 at 37°C and were collected for
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