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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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IsoQC is the major pE1-CCL2 forming enzyme in vivoAnalysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from QC−/− mice compared to WT littermates (QC+/+; n = 4–5, mean ± SEM).Analysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from isoQC−/− mice compared to WT littermates (isoQC+/+; ***p < 0.001 vs. isoQC+/+, Student's t-test, n = 4, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male QC−/− mice compared to WT littermates (QC+/+; n = 6–7, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male isoQC−/− mice, compared to WT littermates (QC+/+; ***p < 0.001 vs. isoQC+/+ +LPS, Student's t-test, n = 5–8, mean ± SEM).IsoQC-deficiency leads to impaired monocyte recruitment to lungs after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; *p < 0.05 vs. isoQC+/+ +LPS, Student's t-test, n = 7–8, mean ± SEM).Analysis of neutrophils in bronchoalveolar fluid after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; n = 7–8, mean ± SEM).
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fig02: IsoQC is the major pE1-CCL2 forming enzyme in vivoAnalysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from QC−/− mice compared to WT littermates (QC+/+; n = 4–5, mean ± SEM).Analysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from isoQC−/− mice compared to WT littermates (isoQC+/+; ***p < 0.001 vs. isoQC+/+, Student's t-test, n = 4, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male QC−/− mice compared to WT littermates (QC+/+; n = 6–7, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male isoQC−/− mice, compared to WT littermates (QC+/+; ***p < 0.001 vs. isoQC+/+ +LPS, Student's t-test, n = 5–8, mean ± SEM).IsoQC-deficiency leads to impaired monocyte recruitment to lungs after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; *p < 0.05 vs. isoQC+/+ +LPS, Student's t-test, n = 7–8, mean ± SEM).Analysis of neutrophils in bronchoalveolar fluid after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; n = 7–8, mean ± SEM).

Mentions: Primary cells isolated from QC−/− mice secreted equal amounts of CCL2(pE1-76) and total-CCL2 into the conditioned medium after LPS-stimulation (Fig 2A). In contrast, a significantly reduced concentration of CCL2(pE1-76) has been observed in conditioned medium of primary cells isolated from isoQC−/− mice after LPS stimulation (Fig 2B).


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)

IsoQC is the major pE1-CCL2 forming enzyme in vivoAnalysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from QC−/− mice compared to WT littermates (QC+/+; n = 4–5, mean ± SEM).Analysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from isoQC−/− mice compared to WT littermates (isoQC+/+; ***p < 0.001 vs. isoQC+/+, Student's t-test, n = 4, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male QC−/− mice compared to WT littermates (QC+/+; n = 6–7, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male isoQC−/− mice, compared to WT littermates (QC+/+; ***p < 0.001 vs. isoQC+/+ +LPS, Student's t-test, n = 5–8, mean ± SEM).IsoQC-deficiency leads to impaired monocyte recruitment to lungs after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; *p < 0.05 vs. isoQC+/+ +LPS, Student's t-test, n = 7–8, mean ± SEM).Analysis of neutrophils in bronchoalveolar fluid after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; n = 7–8, mean ± SEM).
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fig02: IsoQC is the major pE1-CCL2 forming enzyme in vivoAnalysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from QC−/− mice compared to WT littermates (QC+/+; n = 4–5, mean ± SEM).Analysis of the ratio of total-CCL2 and pE1-CCL2 secreted from LPS-stimulated primary cells isolated from isoQC−/− mice compared to WT littermates (isoQC+/+; ***p < 0.001 vs. isoQC+/+, Student's t-test, n = 4, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male QC−/− mice compared to WT littermates (QC+/+; n = 6–7, mean ± SEM).pE1-CCL2 formation in serum after peripheral injection of LPS in male isoQC−/− mice, compared to WT littermates (QC+/+; ***p < 0.001 vs. isoQC+/+ +LPS, Student's t-test, n = 5–8, mean ± SEM).IsoQC-deficiency leads to impaired monocyte recruitment to lungs after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; *p < 0.05 vs. isoQC+/+ +LPS, Student's t-test, n = 7–8, mean ± SEM).Analysis of neutrophils in bronchoalveolar fluid after intranasal LPS-application in isoQC−/− compared to WT littermates (isoQC+/+; n = 7–8, mean ± SEM).
Mentions: Primary cells isolated from QC−/− mice secreted equal amounts of CCL2(pE1-76) and total-CCL2 into the conditioned medium after LPS-stimulation (Fig 2A). In contrast, a significantly reduced concentration of CCL2(pE1-76) has been observed in conditioned medium of primary cells isolated from isoQC−/− mice after LPS stimulation (Fig 2B).

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