Identification of IP-9, a novel CXC-chemokine expressed by keratinocytes

Tensen, Cornelis P.; Flier, Jacoba; Raaij-Helmer, Elizabeth M.H. van der; Sampat-Sardjoepersad, Shakun C.; Schors, B.C. van der; Leurs, Rob; Scheper, Rik J.; Boorsma, D. M.; Willemze, Rein

doi:10.1016/s0923-1811(98)83163-0

Cited by 4 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GTP␥S Binding-CXCR3-expressing CHO cells (24) were scraped in their medium, pelleted, and resuspended in GTP␥S binding buffer (20 mM HEPES, 100 mM NaCl, 5 mM MgCl 2 , 0.1% bovine serum albumin, pH 7.4), containing 1 mM EDTA. Cells were kept on ice for 20 min and subsequently sonicated (2 ϫ 15 s, with 2-min interval).…”

Section: Application Of Proteinase Inhibitors In Keratinocytementioning

confidence: 99%

“…Cells were kept on ice for 20 min and subsequently sonicated (2 ϫ 15 s, with 2-min interval). Large cellular debris was removed by centrifugation at 200 ϫ g. Cell membranes were pelleted from the supernatant at 48,000 ϫ g and resuspended in GTP␥S binding buffer and incubated ( Ca 2ϩ Mobilization-Intracellular calcium mobilization was measured as described previously (24). In brief, CHO cells stably transfected with human CXCR3 were loaded with 1 mM Fura-2 acetoxymethyl esther (Molecular Probes, Leiden, The Netherlands).…”

Section: Application Of Proteinase Inhibitors In Keratinocytementioning

confidence: 99%

“…Chemotaxis-Human peripheral blood T-cells were isolated from buffy coats of healthy donors and stimulated with IL-2 (100 units/ml) and PHA (1 mg/ml) to induce CXCR3 expression, as described previously (24). Chemotaxis of these cells toward chemokines was studied using a Transwell assay starting with 5 ϫ 10 6 cells/100 l for each individual assay.…”

Section: Application Of Proteinase Inhibitors In Keratinocytementioning

confidence: 99%

“…Keratinocytes-We have previously shown that stimulation of human keratinocytes with IFN-␥ induces the production of the CXCR3 targeting chemokines CXCL9, -10, and -11 (24). Following heparin affinity chromatography these chemokines can be purified by reversed-phase chromatography (Fig.…”

Section: Production Of Cxcl10 By Ifn-␥-stimulated Primary Humanmentioning

confidence: 99%

See 3 more Smart Citations

Furin Is a Chemokine-modifying Enzyme

Hensbergen

Verzijl

Balog

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Chemokines comprise a class of structurally related proteins that are involved in many aspects of leukocyte migration under basal and inflammatory conditions. In addition to the large number of genes, limited processing of these proteins by a variety of enzymes enhances the complexity of the total spectrum of chemokine variants. We have recently shown that the native chemokine CXCL10 is processed at the C terminus, thereby shedding the last four amino acids. The present study was performed to elucidate the mechanism in vivo and in vitro and to study the biological activity of this novel isoform of CXCL10. Using a combination of protein purification and mass spectrometric techniques, we show that the production of C-terminally truncated CXCL10 by primary keratinocytes is inhibited in vivo by a specific inhibitor of pro-protein convertases (e.g. furin) but not by inhibition of matrix metalloproteinases. Moreover, CXCL10 is processed by furin in vitro, which is abrogated by a mutation in the furin recognition site. Using GTP␥S binding, Ca 2؉ mobilization, and chemotaxis assays, we demonstrate that the C-terminally truncated CXCL10 variant is a potent ligand for CXCR3. Moreover, the inverse agonist activity on the virally encoded receptor ORF74 and the direct antibacterial activity of CXCL10 are fully retained. Hence, we have identified furin as a novel chemokine-modifying enzyme in vitro and most probably also in vivo, generating a C-terminally truncated CXCL10, which fully retains its (inverse) agonistic properties.

show abstract

Section: Application Of Proteinase Inhibitors In Keratinocytementioning

confidence: 99%

Section: Application Of Proteinase Inhibitors In Keratinocytementioning

confidence: 99%

Section: Application Of Proteinase Inhibitors In Keratinocytementioning

confidence: 99%

Section: Production Of Cxcl10 By Ifn-␥-stimulated Primary Humanmentioning

confidence: 99%

See 2 more Smart Citations

Furin Is a Chemokine-modifying Enzyme

Hensbergen

Verzijl

Balog

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Protease-induced changes in receptor selectivity have consequences for the type of cells that will be attracted and/or activated by the chemokines. Chemokines were isolated as both intact and truncated forms from natural sources (11)(12)(13)(14)(15)(16)(17). Thus, secreted and cell surface peptidases, by their ability to remove N-terminal amino acids, contribute to the regulation of cell traffic.…”

mentioning

confidence: 99%

Kinetic Investigation of Chemokine Truncation by CD26/Dipeptidyl Peptidase IV Reveals a Striking Selectivity within the Chemokine Family

Lambeir¹,

Proost²,

Durinx³

et al. 2001

Journal of Biological Chemistry

256

211

View full text Add to dashboard Cite

Chemokines coordinate many aspects of leukocyte migration. As chemoattractants they play an important role in the innate and acquired immune response. There is good experimental evidence that N-terminal truncation by secreted or cell surface proteases is a way of modulating chemokine action. The localization of CD26/ dipeptidyl peptidase IV on cell surfaces and in biological fluids, its primary specificity, and the type of naturally occurring truncated chemokines are consistent with such a function.We determined the steady-state catalytic parameters for a relevant selection of chemokines (CCL3b, CCL5, CCL11, CCL22, CXCL9, CXCL10, CXCL11, and CXCL12) previously reported to alter their chemotactic behavior due to CD26/dipeptidyl peptidase IV-catalyzed truncation. The results reveal a striking selectivity for stromal cell-derived factor-1␣ (CXCL12) and macrophage-derived chemokine (CCL22). The kinetic parameters support the hypothesis that CD26/dipeptidyl peptidase IV contributes to the degradation of certain chemokines in vivo. The data not only provide insight into the selectivity of the enzyme for specific chemokines, but they also contribute to the general understanding of CD26/dipeptidyl peptidase IV secondary substrate specificity.

show abstract

Synthesis and Structure‐Activity Relationships of 3H‐Quinazolin‐4‐ones and 3H‐Pyrido[2,3‐d]pyrimidin‐4‐ones as CXCR3 receptor antagonists

Storelli

Verzijl

Al‐Badie

et al. 2007

Archiv der Pharmazie

View full text Add to dashboard Cite

CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethyl}-(2-dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions.

show abstract

Identification of IP-9, a novel CXC-chemokine expressed by keratinocytes

Cited by 4 publications

References 0 publications

Furin Is a Chemokine-modifying Enzyme

Furin Is a Chemokine-modifying Enzyme

Kinetic Investigation of Chemokine Truncation by CD26/Dipeptidyl Peptidase IV Reveals a Striking Selectivity within the Chemokine Family

Synthesis and Structure‐Activity Relationships of 3H‐Quinazolin‐4‐ones and 3H‐Pyrido[2,3‐d]pyrimidin‐4‐ones as CXCR3 receptor antagonists

Contact Info

Product

Resources

About