Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4

Valenzuela-Fernández, Agustı́n; Planchenault, Thierry; Baleux, Françoise; Staropoli, Isabelle; Le-Barillec, Karine; Leduc, Dominique; Delaunay, Thierry; Lazarini, Françoise; Virelizier, Jean-Louis; Chignard, Michel; Pidard, Dominique; Arenzana-Seisdedos, Fernando

doi:10.1074/jbc.m111388200

Cited by 198 publications

(163 citation statements)

References 92 publications

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“…Since production of SDF-1 in the marrow of Gata1 low mice is not higher than normal (Figure 1), entrapment of SDF-1 within the increased number of mutant megakaryocytes reduces the amount of SDF-1 available for other cells in the marrow. Furthermore, since SDF-1 is very sensitive to protease degradation [27][28][29][30] and both the full length and its proteolytic products 58 are recognized by immunostaining, it is possible that the high levels of SDF-1 observed in the marrow both of Gata1 low mice and PV patients represent proteolytically cleaved SDF-1. In summary, it is possible that, in spite of high levels of SDF-1 immunostaining, the marrow of the animal model and of the PMF patients is deprived of functional SDF-1 because of increased SDF-1 uptake by the high numbers of defective megakaryocytes and presence of inactive degradation products of SDF-1 bound to the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

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Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

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Section: Discussionmentioning

confidence: 99%

“…In fact, under steady-state conditions, the levels of soluble SDF-1 present in the blood of younger animals are low. SDF-1 is very sensitive to protease degradation [27][28][29][30] .…”

Section: Introductionmentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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“…Intracellular calcium levels were measured in a fluorescence spectrophotometer (Eclypse Variant; Melbourne, Australia) using Fura 2-AM (5 M)-loaded CEM.NKR-CCR5 cells (5 ϫ 10 6 cells/ml), as similarly described (25). Briefly, cells were resuspended in Hanks' balanced salt solution buffer (140 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 1 mM MgSO 4 , …”

Section: Measurement Of Cytosolic Free Calciummentioning

confidence: 99%

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

Barroso-González

Jaber-Vazdekis

García-Expósito

et al. 2009

Journal of Biological Chemistry

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The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-Oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with ␤-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxocalenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle. The human immunodeficiency virus (HIV)7 pandemic is a medical challenge and represents the public health crisis of our time (1-5). Antiretroviral treatment achieves long-lasting viral suppression and, subsequently, reduces the morbidity and mortality of HIV-infected individuals. However, current drugs do not eradicate HIV infection and lifelong treatment might be needed (2).Emerging drug-resistant HIV viruses, in patients receiving high active antiretroviral treatment, urgently needs the development of new antiretroviral molecules designed to inhibit resistant viruses, because many patients treated during the past decades harbor viral strains with reduced susceptibilities to many if not all available drugs (2, 6). In this matter, pentacyclic triterpenes represent a varied class of natural products presenting antitumor and antiviral activities (7-9). A well studied pentacyclic lupane-type triterpene is the betulinic acid (3␤-hydroxy-lup-20(29)-en-28-oic acid), widely distributed throughout the plant kingdom, which presents anti-inflammatory, anti-malarial, and anti-HIV-1 effects in vitro (7, 9, 10). Although its mechanism of action has not been f...

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“…Our attempts to evaluate whether SDF-1 is potentially functional disclosed NH 2 -terminally intact SDF-1. This was detected by ELISA using a capture K15c mAb (26). We found that in AML patients, in contrast to total SDF-1, the levels of intact SDF-1 in the peripheral blood (Fig.…”

Section: Resultsmentioning

confidence: 87%

“…Total SDF-1 levels in tested samples were determined by ELISA as described (27). To measure levels of intact, noncleaved SDF-1, we applied the K15c mAb as a capture antibody (10 Ag/mL; INRA) that recognizes an epitope containing the first three amino acids of SDF-1 (26).…”

Section: Methodsmentioning

confidence: 99%

Functional CXCR4-Expressing Microparticles and SDF-1 Correlate with Circulating Acute Myelogenous Leukemia Cells

et al. 2006

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Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are implicated in the pathogenesis and prognosis of acute myelogenous leukemia (AML). Cellular microparticles, submicron vesicles shed from the plasma membrane of various cells, are also associated with human pathology. In the present study, we investigated the putative relationships between the SDF-1/CXCR4 axis and microparticles in AML. We detected CXCR4-expressing microparticles (CXCR4 + microparticles) in the peripheral blood and bone marrow plasma samples of normal donors and newly diagnosed adult AML patients. In samples from AML patients, levels of CXCR4 + microparticles and total SDF-1 were elevated compared with normal individuals. The majority of CXCR4 + microparticles in AML patients were CD45 + , whereas in normal individuals, they were mostly CD41 + . Importantly, we found a strong correlation between the levels of CXCR4 + microparticle and WBC count in the peripheral blood and bone marrow plasma obtained from the AML patients. Of interest, levels of functional, noncleaved SDF-1 were reduced in these patients compared with normal individuals and also strongly correlated with the WBC count. Furthermore, our data indicate NH 2 -terminal truncation of the CXCR4 molecule in the microparticles of AML patients. However, such microparticles were capable of transferring the CXCR4 molecule to AML-derived HL-60 cells, enhancing their migration to SDF-1 in vitro and increasing their homing to the bone marrow of irradiated NOD/SCID/B2m null mice. The CXCR4 antagonist AMD3100 reduced these effects. Our findings suggest that functional CXCR4 + microparticles and SDF-1 are involved in the progression of AML. We propose that their levels are potentially valuable as an additional

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Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4

Cited by 198 publications

References 92 publications

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

Functional CXCR4-Expressing Microparticles and SDF-1 Correlate with Circulating Acute Myelogenous Leukemia Cells

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