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The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions.

Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, Rahfeld JU, Wolf R, Wermann M, Stephan A, Haegele M, Sedlmeier R, Graubner S, Jagla W, Müller A, Eichentopf R, Heiser U, Seifert F, Quax PH, de Vries MR, Hesse I, Trautwein D, Wollert U, Berg S, Freyse EJ, Schilling S, Demuth HU - EMBO Mol Med (2011)

Bottom Line: Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration.Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers.The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Probiodrug AG, Halle, Germany.

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Pharmacological inhibition of QC/isoQC activity in vitro and in vivo reduces pE-CCL2 activityAnalysis of total-CCL2 (black bars) and pE1-CCL2 (open bars) after application of varying doses PQ529 to LPS-stimulated primary murine glia cells isolated from C57BL/6J WT mice compared to unstimulated controls (***p < 0.001 vs. pE1-CCL2 (0 µM PQ529), ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Analysis of CCL2 gene expression in LPS-stimulated primary glia cells derived from Fig 4A(*p < 0.05, **p < 0.01 vs. PQ529 0 µM, ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Representative FACS image showing the reduction of infiltrating monocytes after application of PQ529 (30 mg/kg, i.p.).Dose-dependent reduction of infiltrating monocytes in absence (black bars) or presence (red bars) of intraperitoneal PQ529 treatment (**p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).Inhibition of monocyte infiltration after oral application of PQ50 (red bars) and PQ529 (white bar; **p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).
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fig04: Pharmacological inhibition of QC/isoQC activity in vitro and in vivo reduces pE-CCL2 activityAnalysis of total-CCL2 (black bars) and pE1-CCL2 (open bars) after application of varying doses PQ529 to LPS-stimulated primary murine glia cells isolated from C57BL/6J WT mice compared to unstimulated controls (***p < 0.001 vs. pE1-CCL2 (0 µM PQ529), ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Analysis of CCL2 gene expression in LPS-stimulated primary glia cells derived from Fig 4A(*p < 0.05, **p < 0.01 vs. PQ529 0 µM, ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Representative FACS image showing the reduction of infiltrating monocytes after application of PQ529 (30 mg/kg, i.p.).Dose-dependent reduction of infiltrating monocytes in absence (black bars) or presence (red bars) of intraperitoneal PQ529 treatment (**p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).Inhibition of monocyte infiltration after oral application of PQ50 (red bars) and PQ529 (white bar; **p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).

Mentions: In a first approach, primary murine glia cells were isolated and stimulated using LPS. As expected, the stimulation of the primary cells resulted in a significant increase in CCL2 within the medium. The inhibitor PQ529 decreased the concentration of pE1-CCL2 dose-dependently (Fig 4A). Thereby, the inhibitor led to a slight but significant increase of CCL2 mRNA for the doses of 0.625 and 2.5 µM (Fig 4B), however, PQ529 did not show an effect on CCL2 expression in LPS-stimulated THP-1 cells (Fig 7A of Supporting Information). Similar to treatment of the primary glia cells, PQ529 reduced pE1-CCL2 secreted from murine and human primary macrophages (Fig 6A and B of Supporting Information).


The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions.

Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, Rahfeld JU, Wolf R, Wermann M, Stephan A, Haegele M, Sedlmeier R, Graubner S, Jagla W, Müller A, Eichentopf R, Heiser U, Seifert F, Quax PH, de Vries MR, Hesse I, Trautwein D, Wollert U, Berg S, Freyse EJ, Schilling S, Demuth HU - EMBO Mol Med (2011)

Pharmacological inhibition of QC/isoQC activity in vitro and in vivo reduces pE-CCL2 activityAnalysis of total-CCL2 (black bars) and pE1-CCL2 (open bars) after application of varying doses PQ529 to LPS-stimulated primary murine glia cells isolated from C57BL/6J WT mice compared to unstimulated controls (***p < 0.001 vs. pE1-CCL2 (0 µM PQ529), ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Analysis of CCL2 gene expression in LPS-stimulated primary glia cells derived from Fig 4A(*p < 0.05, **p < 0.01 vs. PQ529 0 µM, ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Representative FACS image showing the reduction of infiltrating monocytes after application of PQ529 (30 mg/kg, i.p.).Dose-dependent reduction of infiltrating monocytes in absence (black bars) or presence (red bars) of intraperitoneal PQ529 treatment (**p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).Inhibition of monocyte infiltration after oral application of PQ50 (red bars) and PQ529 (white bar; **p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).
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fig04: Pharmacological inhibition of QC/isoQC activity in vitro and in vivo reduces pE-CCL2 activityAnalysis of total-CCL2 (black bars) and pE1-CCL2 (open bars) after application of varying doses PQ529 to LPS-stimulated primary murine glia cells isolated from C57BL/6J WT mice compared to unstimulated controls (***p < 0.001 vs. pE1-CCL2 (0 µM PQ529), ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Analysis of CCL2 gene expression in LPS-stimulated primary glia cells derived from Fig 4A(*p < 0.05, **p < 0.01 vs. PQ529 0 µM, ANOVA followed by Tukey post hoc test, n = 3–4, mean ± SEM).Representative FACS image showing the reduction of infiltrating monocytes after application of PQ529 (30 mg/kg, i.p.).Dose-dependent reduction of infiltrating monocytes in absence (black bars) or presence (red bars) of intraperitoneal PQ529 treatment (**p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).Inhibition of monocyte infiltration after oral application of PQ50 (red bars) and PQ529 (white bar; **p < 0.01 vs. Thio (+), ANOVA followed by Tukey post hoc test, n = 5–6, mean ± SEM, female mice).
Mentions: In a first approach, primary murine glia cells were isolated and stimulated using LPS. As expected, the stimulation of the primary cells resulted in a significant increase in CCL2 within the medium. The inhibitor PQ529 decreased the concentration of pE1-CCL2 dose-dependently (Fig 4A). Thereby, the inhibitor led to a slight but significant increase of CCL2 mRNA for the doses of 0.625 and 2.5 µM (Fig 4B), however, PQ529 did not show an effect on CCL2 expression in LPS-stimulated THP-1 cells (Fig 7A of Supporting Information). Similar to treatment of the primary glia cells, PQ529 reduced pE1-CCL2 secreted from murine and human primary macrophages (Fig 6A and B of Supporting Information).

Bottom Line: Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration.Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers.The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Probiodrug AG, Halle, Germany.

Show MeSH
Related in: MedlinePlus