scholarly journals Activation of Lipoxin a4 Receptors by Aspirin-Triggered Lipoxins and Select Peptides Evokes Ligand-Specific Responses in Inflammation

2000 ◽  
Vol 191 (7) ◽  
pp. 1197-1208 ◽  
Author(s):  
Nan Chiang ◽  
Iolanda M. Fierro ◽  
Karsten Gronert ◽  
Charles N. Serhan
Keyword(s):  
Tissue Injury ◽  
Leukotriene B4 ◽  
Peptide Ligands ◽  
Peptide Fragments ◽  
Transmembrane Segment ◽  
Small Peptides ◽  
Lipoxin A4 ◽  
Chimeric Receptors ◽  
Chemotactic Peptides ◽  
Endogenous Lipids

Lipoxin (LX) A4 and aspirin-triggered LX (ATL) are endogenous lipids that regulate leukocyte trafficking via specific LXA4 receptors (ALXRs) and mediate antiinflammation and resolution. ATL analogues dramatically inhibited human neutrophil (polymorphonuclear leukocyte [PMN]) responses evoked by a potent necrotactic peptide derived from mitochondria as well as a rogue synthetic chemotactic peptide. These bioactive lipid analogues and small peptides each selectively competed for specific 3H-LXA4 binding with recombinant human ALXR, and its N-glycosylation proved essential for peptide but not LXA4 recognition. Chimeric receptors constructed from receptors with opposing functions, namely ALXR and leukotriene B4 receptors (BLTs), revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA4 recognition, and additional regions of ALXR are required for high affinity binding of the peptide ligands. Together, these findings are the first to indicate that a single seven-transmembrane receptor can switch recognition as well as function with certain chemotactic peptides to inhibitory with ATL and LX (lipid ligands). Moreover, they suggest that ALXR activation by LX or ATL can protect the host from potentially deleterious PMN responses associated with innate immunity as well as direct effector responses in tissue injury by recognition of peptide fragments.

scholarly journals 5-LO-derived LTB4 plays a key role in MCP-1 expression in HMGB1-exposed VSMCs via a BLTR1 signaling axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jong Min Choi ◽  
Seung Eun Baek ◽  
Ji On Kim ◽  
Eun Yeong Jeon ◽  
Eun Jeong Jang ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Vascular Inflammation ◽  
High Mobility ◽  
Leukotriene B4 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Signaling Axis ◽  
Cellular Source ◽  
Leukotriene Receptor ◽  
In Cells

AbstractMonocyte chemoattractant protein-1 (MCP-1) plays an important role in initiating vascular inflammation; however, its cellular source in the injured vasculatures is unclear. Given the importance of high mobility group box 1 (HMGB1) in tissue injury, we investigated the role of vascular smooth muscle cells (VSMCs) in MCP-1 production in response to HMGB1. In primary cultured rat aortic VSMCs stimulated with HMGB1, the expression of MCP-1 and 5-lipoxygenase (LO) was increased. The increased MCP-1 expression in HMGB1 (30 ng/ml)-stimulated cells was significantly attenuated in 5-LO-deficient cells as well as in cells treated with zileuton, a 5-LO inhibitor. Likewise, MCP-1 expression and production were also increased in cells stimulated with exogenous leukotriene B4 (LTB4), but not exogenous LTC4. LTB4-induced MCP-1 expression was attenuated in cells treated with U75302, a LTB4 receptor 1 (BLTR1) inhibitor as well as in BLTR1-deficient cells, but not in 5-LO-deficient cells. Moreover, HMGB1-induced MCP-1 expression was attenuated in BLTR1-deficient cells or by treatment with a BLTR1 inhibitor, but not other leukotriene receptor inhibitors. In contrast to MCP-1 expression in response to LTB4, the increased MCP-1 production in HMGB1-stimulated VSMC was markedly attenuated in 5-LO-deficient cells, indicating a pivotal role of LTB4-BLTR1 signaling in MCP-1 expression in VSMCs. Taken together, 5-LO-derived LTB4 plays a key role in MCP-1 expression in HMGB1-exposed VSMCs via BLTR1 signaling, suggesting the LTB4-BLTR1 signaling axis as a potential therapeutic target for vascular inflammation in the injured vasculatures.

scholarly journals Lipoxin A4 induces hyperadhesiveness in human endothelial cells for neutrophils

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 948-953 ◽  
Author(s):  
R Lerner ◽  
M Heimburger ◽  
J Palmblad
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
Cytosolic Calcium ◽  
Leukotriene B4 ◽  
Polymorphonuclear Neutrophil ◽  
Maximal Response ◽  
Neutrophil Granulocytes ◽  
Lipoxin A4

Abstract Lipoxin A4 (LXA4), but not lipoxin B4, induced in vitro a dose- dependent, slowly emerging hyperadhesiveness in human umbilical vein endothelial cells (HUVEC), leading to a 1.9-fold increase in the binding of neutrophils (polymorphonuclear neutrophil granulocytes [PMN]). The maximal response to LXA4 occurred at 1 nmol/L and after 30 minutes of treatment of HUVEC. These response kinetics were intermediate in comparison with those of fast-acting inducers of HUVEC adhesivity (eg, thrombin, leukotriene B4 [LTB4] or platelet activating factor [PAF]), needing 5 to 15 minutes, or to the slow inducer interleukin-1 (IL-1 beta), which requires hours. The maximal LXA4 effect was slightly lower than that of LTB4 (100 nmol/L) and thrombin (1 U/mL), and less than that of PAF (100 nmol/L) or IL-1 beta (2.5 U/mL) (2.2-, 2.0-, 2.4-, or 13.6-fold increases, respectively). The LXA4 effect was inhibited by the PAF receptor antagonist WEB-2086; however, it could not be blocked by pertussis toxin. LXA4 conferred a slow, sustained increase in HUVEC cytosolic calcium ion concentrations, whereas thrombin did so rapidly and transiently. LXA4 also caused PMN to become hyperadhesive. Thus, this novel effect of LXA4 on HUVEC appears to be associated with endogenous PAF expression and slow increases of cytosolic calcium concentrations but not pertussis- sensitive G proteins.

Leukotrienes stimulate neutrophil adhesion to mesangial cells: modulation with lipoxins

1990 ◽  
Vol 259 (5) ◽  
pp. F809-F815 ◽  
Author(s):  
H. R. Brady ◽  
U. Persson ◽  
B. J. Ballermann ◽  
B. M. Brenner ◽  
C. N. Serhan
Keyword(s):  
High Performance ◽  
Mesangial Cells ◽  
Divalent Cations ◽  
Leukotriene B4 ◽  
Polymorphonuclear Neutrophil ◽  
Induced Response ◽  
Lipoxin A4 ◽  
Leukotriene D4 ◽  
Adhesion Process

We have examined polymorphonuclear neutrophil (PMN) adhesion to mesangial cells (MC) in vitro and have assessed the actions of lipoxygenase (LO) products in this process. On exposure to either leukotriene B4 (LTB4), or leukotriene D4 (LTD4), 111In-labeled PMNs adhere to monolayers of cultured MC. These actions were rapid in onset (less than 5 min) and dependent upon leukotriene concentration (10(-9) to 10(-6) M) and the presence of divalent cations. Adhesion was sustained (0-30 min), and neither LTB4 nor LTD4 was metabolized to inactive products during PMN-MC interaction, as determined by their recovery after reverse-phase high-performance liquid chromatography. LTB4 was a PMN-directed stimulus, whereas LTD4 appeared to act on MC. A monoclonal antibody (TS 1/18) against the CD18 component of the PMN CD18/CD11 adhesion complex inhibited the LTB4-induced response, indicating involvement of this PMN glycoprotein in the adhesion process. In contrast, this antibody did not affect LTD4-induced adhesion, suggesting that this response was mediated by other adhesion epitopes. When added alone, neither lipoxin A4 (LXA4) nor lipoxin B4 (LXB4) provoked PMN adhesion to MC. In contrast, LXA4 and LXB4 at equimolar concentrations attenuated the LTD4- but not LTB4-induced response. Together, these results provide further evidence that LO-derived eicosanoids may constitute important early signals that regulate PMN-MC interaction in glomerular inflammation.

scholarly journals The distribution of different molecular species of collagen in fibrous, elastic and hyaline cartilages of the pig

1975 ◽  
Vol 151 (3) ◽  
pp. 595-602 ◽  
Author(s):  
D R Eyre ◽  
H Muir
Keyword(s):  
Column Chromatography ◽  
Cyanogen Bromide ◽  
Sodium Dodecyl ◽  
Type Ii Collagen ◽  
Type I ◽  
Type Ii ◽  
Peptide Fragments ◽  
Synovial Joint ◽  
Small Peptides ◽  
Elastic Cartilage

The distribution of type II collagen, considered to be characteristic of cartilaginous tissues, was determined in various specialized cartilages of the mature pig. The tissues examined were: (1) fibrocartilage of the semilunar meniscus of the knee; (2) elastic cartilage of the external ear; (3) hyaline cartilage of (a) the synovial joint (b) the thyroid plate of the larynx, and (c) the nasal septum. The predominant species of collagen in each tissue, whether type I or type II, was appraised semi-quantitatively by analysis of purified collagen solubilized by pepsin and of peptide fragments produced by cyanogen bromide. Cyanogen bromide-derived peptides were characterized by column chromatography on CM-cellulose and by electrophoresis in sodium dodecyl sulphate-polyacrylamide gels. The proportion of each type of collagen was determined precisely by isolating the homologous small peptides α1(II)CB6 [nomenclature of Miller (1973) Clin. Orthop. 92, 260-280], by column chromatography on phosphocellulose and determining their relative proportions by amino acid analysis. Thus collagen of the fibrocartilage of the meniscus proved to be all type I; type II was not detected. In contrast, collagen of elastic cartilage of the outer ear, after rigorous exclusion of perichondrium, was type II. Similarly, type II was the only collagen detected in all the mature hyalline cartilages examined.

scholarly journals Lipoxin A4 induces hyperadhesiveness in human endothelial cells for neutrophils

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 948-953
Author(s):  
R Lerner ◽  
M Heimburger ◽  
J Palmblad
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
Cytosolic Calcium ◽  
Leukotriene B4 ◽  
Polymorphonuclear Neutrophil ◽  
Maximal Response ◽  
Neutrophil Granulocytes ◽  
Lipoxin A4

Lipoxin A4 (LXA4), but not lipoxin B4, induced in vitro a dose- dependent, slowly emerging hyperadhesiveness in human umbilical vein endothelial cells (HUVEC), leading to a 1.9-fold increase in the binding of neutrophils (polymorphonuclear neutrophil granulocytes [PMN]). The maximal response to LXA4 occurred at 1 nmol/L and after 30 minutes of treatment of HUVEC. These response kinetics were intermediate in comparison with those of fast-acting inducers of HUVEC adhesivity (eg, thrombin, leukotriene B4 [LTB4] or platelet activating factor [PAF]), needing 5 to 15 minutes, or to the slow inducer interleukin-1 (IL-1 beta), which requires hours. The maximal LXA4 effect was slightly lower than that of LTB4 (100 nmol/L) and thrombin (1 U/mL), and less than that of PAF (100 nmol/L) or IL-1 beta (2.5 U/mL) (2.2-, 2.0-, 2.4-, or 13.6-fold increases, respectively). The LXA4 effect was inhibited by the PAF receptor antagonist WEB-2086; however, it could not be blocked by pertussis toxin. LXA4 conferred a slow, sustained increase in HUVEC cytosolic calcium ion concentrations, whereas thrombin did so rapidly and transiently. LXA4 also caused PMN to become hyperadhesive. Thus, this novel effect of LXA4 on HUVEC appears to be associated with endogenous PAF expression and slow increases of cytosolic calcium concentrations but not pertussis- sensitive G proteins.

scholarly journals Heterogeneity of human polymorphonuclear leukocyte receptors for leukotriene B4. Identification of a subset of high affinity receptors that transduce the chemotactic response.

1984 ◽  
Vol 159 (4) ◽  
pp. 1027-1041 ◽  
Author(s):  
D W Goldman ◽  
E J Goetzl
Keyword(s):  
Specific Binding ◽  
Leukotriene B4 ◽  
Chemotactic Response ◽  
Structural Isomers ◽  
Human Polymorphonuclear Leukocyte ◽  
High Affinity ◽  
Pmn Leukocytes ◽  
Chemotactic Peptides ◽  
Computer Analyses ◽  
Pmn Leukocyte

Human polymorphonuclear (PMN) leukocytes bound [3H]leukotriene B4 ([3H]-LTB4) specifically, as assessed by the displacement of 88% or more of the bound radioactivity by a 15,000-fold higher concentration of nonradioactive LTB4 or by micromolar concentrations of structural isomers of LTB4. The specific binding of [3H]LTB4 by PMN leukocytes was characterized by rapid association and dissociation, and was saturable at 800 nM LTB4. The results of computer analyses of the concentration dependence of binding of [3H]LTB4 were consistent with the expression of two classes of receptors having respective mean affinities of 3.9 X 10(-10) M and 6.1 X 10(-8) M and mean densities of 4.4 X 10(3) and 2.7 X 10(5) per PMN leukocyte. Structural isomers of LTB4 inhibited the binding of [3H]LTB4 to PMN leukocytes at concentrations similar to those required to elicit chemotaxis, while chemotactic peptides did not inhibit binding. PMN leukocytes that were deactivated by prior exposure to LTB4 lost high affinity binding sites selectively and concurrently with a reduction in the chemotactic response to LTB4. Chemotactic deactivation altered, but did not eliminate, the low affinity receptors for LTB4 and reduced only minimally the lysosomal degranulation elicited by LTB4. The high affinity receptors for LTB4 on normal human PMN leukocytes appear to transduce the chemotaxis evoked by LTB4 without substantially modifying lysosomal degranulation.

scholarly journals Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis

2014 ◽  
Vol 44 (2) ◽  
pp. 394-404 ◽  
Author(s):  
F. C. Ringholz ◽  
P. J. Buchanan ◽  
D. T. Clarke ◽  
R. G. Millar ◽  
M. McDermott ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Leukotriene B4 ◽  
Lipoxin A4

scholarly journals Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing

2007 ◽  
Vol 204 (2) ◽  
pp. 245-252 ◽  
Author(s):  
Camilla I. Svensson ◽  
Michela Zattoni ◽  
Charles N. Serhan
Keyword(s):  
Tissue Injury ◽  
Spinal Pain ◽  
Pain Processing ◽  
Lipoxin A4 ◽  
Inflammatory Conditions ◽  
Extracellular Signal ◽  
Inflammatory State

Inflammatory conditions can lead to debilitating and persistent pain. This hyperalgesia reflects sensitization of peripheral terminals and facilitation of pain signaling at the spinal level. Studies of peripheral systems show that tissue injury triggers not only inflammation but also a well-orchestrated series of events that leads to reversal of the inflammatory state. In this regard, lipoxins represent a unique class of lipid mediators that promote resolution of inflammation. The antiinflammatory role of peripheral lipoxins raises the hypothesis that similar neuraxial systems may also down-regulate injury-induced spinal facilitation of pain processing. We report that the lipoxin A4 receptor is expressed on spinal astrocytes both in vivo and in vitro and that spinal delivery of lipoxin A4, as well as stable analogues, attenuates inflammation-induced pain. Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of lipoxins. This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation. Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.

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