Pharmacological Properties of Peptides Derived from Stromal Cell-Derived Factor 1: Study on Human Polymorphonuclear Cells

Heveker, Nikolaus; Tissot, M.; Thuret, Alain; Schneider‐Mergener, Jens; Alizon, Marc; Roch, Monique; Marullo, Stéfano

doi:10.1124/mol.59.6.1418

Cited by 16 publications

(12 citation statements)

References 37 publications

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“…This is only possible because there are at least two distinct binding sites in CXCR4. Short N-terminal CXCR4 or vMIP-II peptides that do not include the N-loop that interacts with the CXCR4 N-terminal region have been shown to be weak agonists or antagonist, respectively (42,(77)(78)(79)(80). Consequently, MIF and CXCL12 compete for binding with the CXCR4 N-terminal region, which is consistent with the 50% maximum displacement of 125 I-CXCL12 by 1 M MIF relative to 100 nM CXCL12 (37).…”

Section: Discussionsupporting

confidence: 57%

Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions

Rajasekaran

Gröning

Schmitz

et al. 2016

Journal of Biological Chemistry

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An emerging number of non-chemokine mediators are found to bind to classical chemokine receptors and to elicit critical biological responses. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exhibits chemokine-like activities through non-cognate interactions with the chemokine receptors CXCR2 and CXCR4, in addition to activating the type II receptor CD74. Activation of the MIF-CXCR2 and -CXCR4 axes promotes leukocyte recruitment, mediating the exacerbating role of MIF in atherosclerosis and contributing to the wealth of other MIF biological activities. Although the structural basis of the MIF-CXCR2 interaction has been well studied and was found to engage a pseudo-ELR and an N-like loop motif, nothing is known about the regions of CXCR4 and MIF that are involved in binding to each other. Using a genetic strain of Saccharomyces cerevisiae that expresses a functional CXCR4 receptor, site-specific mutagenesis, hybrid CXCR3/CXCR4 receptors, pharmacological reagents, peptide array analysis, chemotaxis, fluorescence spectroscopy, and circular dichroism, we provide novel molecular information about the structural elements that govern the interaction between MIF and CXCR4. The data identify similarities with classical chemokine-receptor interactions but also provide evidence for a partial allosteric agonist compared with CXCL12 that is possible due to the two binding sites of CXCR4.

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Section: Discussionsupporting

confidence: 57%

Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions

Rajasekaran

Gröning

Schmitz

et al. 2016

Journal of Biological Chemistry

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“…SDF1␣, which was initially found to stimulate PMN migration and calcium transients (11), failed to induce migration in another study (8). In another work, the PMN chemotactic effect of SDF1␣ was comparable to that of fMLP and C5a, whereas calcium transients were strikingly low (33). To determine whether the low SDF1␣-mediated production of ROS was due to the condition of our PMN preparations, we compared the SDF1␣-and fMLP-induced directed migration of PMN (Fig.…”

Section: Comparison Of the Effects Of Sdf1␣ And Fmlp On Pmn Rb Chemomentioning

confidence: 89%

Stroma Cell-Derived Factor 1α Mediates Desensitization of Human Neutrophil Respiratory Burst in Synovial Fluid from Rheumatoid Arthritic Patients

Lenoir

Djerdjouri

Périanin

2004

The Journal of Immunology

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Classical chemoattractants such as fMLP or the complement factor C5a use G protein (Gi)-coupled receptors to stimulate both chemotaxis and production of reactive oxygen species (respiratory burst, RB) by polymorphonuclear leukocytes (PMN). The chemokine stroma cell-derived factor 1α (SDF1α) and its Gi-coupled receptor, CXCR4, regulate leukocyte trafficking and recruitment to the synovial fluid of rheumatoid arthritic patients (RA-SF). However, the role of SDF1α in the RB is unknown and was studied in this work in vitro with healthy PMN in the absence and presence of RA-SF. In healthy PMN, SDF1α failed to stimulate the RB, even though the p38 mitogen-activated protein kinase was activated to a similar level as in fMLP-stimulated PMN. In contrast, the SDF1α-mediated calcium transients and activation of phosphatidylinositol 3-kinase/Akt were partially deficient, while p44/42 mitogen-activated protein kinases were not activated. SDF1α actually desensitized weakly the fMLP-mediated RB of healthy PMN. This cross-inhibitory effect was amplified in PMN treated with RA-SF, providing a protection against the exacerbation of RB induced by C5a or fMLP. This SDF1α beneficial effect, which was prevented by the CXCR4 antagonist AMD3100, was associated with impairment of C5a- and fMLP-mediated early signaling events. Thus, although SDF1α promotes leukocyte emigration into rheumatoid synovium, our data suggest it cross-desensitizes the production of oxidant by primed PMN, a property that may be beneficial in the context of arthritis.

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“…TC14012, a T140 analogue with similar biological properties, was synthesized as described previously (35). The sequences of the CXCR4 transmembrane domain-derived peptides as described in Tarasova et al (36) were synthesized using Fmoc (N-(9-fluorenyl)methoxycarbonyl) solid phase synthesis as described previously (37), purified to Ͼ95% purity and characterized by matrix-assisted laser desorption ionization/time of flight mass spectrometry. The sequences of the peptides are as follows: CXCR4-TMII, LLFVITLPFWAVDAVANWYFGN-DD-OH; CXCR4-TMIV, VYVGVWIPALLLTIPDFIFANDD-OH; CXCR-4-TMVI, VILILAFFACWLPYYIGISID-OH; CXCR4-TMVII, DDEALA-FFHCCLNPILYAFL-NH 2 .…”

Section: Methodsmentioning

confidence: 99%

Bioluminescence Resonance Energy Transfer Reveals Ligand-induced Conformational Changes in CXCR4 Homo- and Heterodimers

Percherancier

Berchiche

Slight

et al. 2005

Journal of Biological Chemistry

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236

233

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Homo-and heterodimerization have emerged as prominent features of G-protein-coupled receptors with possible impact on the regulation of their activity. Using a sensitive bioluminescence resonance energy transfer system, we investigated the formation of CXCR4 and CCR2 chemokine receptor dimers. We found that both receptors exist as constitutive homo-and heterodimers and that ligands induce conformational changes within the pre-formed dimers without promoting receptor dimer formation or disassembly. Ligands with different intrinsic efficacies yielded distinct bioluminescence resonance energy transfer modulations, indicating the stabilization of distinct receptor conformations. We also found that peptides derived from the transmembrane domains of CXCR4 inhibited activation of this receptor by blocking the ligand-induced conformational transitions of the dimer. Taken together, our data support a model in which chemokine receptor homo-and heterodimers form spontaneously and respond to ligand binding as units that undergo conformational changes involving both protomers even when only one of the two ligand binding sites is occupied.In recent years, the concept of GPCR 1 dimerization has raised questions about the molecular details and functional role of such oligomeric assembly (for a recent review, see Ref.1). Given the clinical interest in GPCRs, insights into the structural and functional organization of the receptor complexes have the potential to facilitate the design of new drug candidates with increased efficacy and selectivity. Resonance energy transfer (RET) techniques have emerged as methods of choice to study receptor dimerization in living cells. Although most RET studies indicate that many if not all GPCRs exist as dimers or higher oligomers under basal conditions, apparent contradictions exist concerning their potential dynamic regulation upon ligand binding. Although numerous authors did not find any effects of ligands on constitutive RET signals in their systems (2-8), others observed ligand-promoted increases or decreases that were interpreted as either the formation (9 -11) or the dissociation (12-15) of GPCR dimers in response to receptor activation. Conformational changes within pre-existing constitutive dimers have also been proposed as alternative explanations for agonist or antagonist-induced changes in .Chemokine receptors such as CCR2 and CXCR4 have been reported to form homo-and heterodimers (3, 4, 19 -24). In early co-immunoprecipitation studies, proposed that the dimerization of CXCR4 is induced upon activation by its chemokine ligand SDF-1. In contrast, data obtained with RET techniques revealed that CXCR4 homo-dimers form spontaneously in the absence of ligand (3,4,24). In one study, no significant effect of SDF-1 was observed on the constitutive energy transfer (4), whereas a small but reproducible increase was detected by others (24). As for CXCR4, agonist stimulation of CCR2 was found to promote the formation of dimers as revealed by chemical cross-linking followed by immunoprecipitati...

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Pharmacological Properties of Peptides Derived from Stromal Cell-Derived Factor 1: Study on Human Polymorphonuclear Cells

Cited by 16 publications

References 37 publications

Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions

Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions

Stroma Cell-Derived Factor 1α Mediates Desensitization of Human Neutrophil Respiratory Burst in Synovial Fluid from Rheumatoid Arthritic Patients

Bioluminescence Resonance Energy Transfer Reveals Ligand-induced Conformational Changes in CXCR4 Homo- and Heterodimers

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