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

Cynis, Holger; Hoffmann, Torsten; Friedrich, Daniel; Kehlen, Astrid; Gans, Kathrin; Kleinschmidt, Martin; Rahfeld, Jens‐Ulrich; Wolf, Reinhard; Wermann, Michael; Stephan, Anett; Haegele, Monique; Sedlmeier, Reinhard; Graubner, Sigrid; Jagla, Wolfgang; Müller, Anke Katharina; Eichentopf, Rico; Heiser, Ulrich; Seifert, F.; Quax, Paul H.A.; Vries, Margreet R. de; Hesse, Isabel; Trautwein, Daniela; Wollert, Ulrich; Berg, Sabine; Freyse, Ernst‐Joachim; Schilling, Stephan; Demuth, Hans‐Ulrich

doi:10.1002/emmm.201100158

Cited by 81 publications

(137 citation statements)

References 53 publications

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“…N-terminal pyroglutamate residues have been described for a number of hormones and secreted proteins (31). For example, the N terminus of monocyte chemoattractant protein 1 (CCL2/MCP-1) is modified to a pyroglutamate residue, thereby protecting it against degradation (32). MCP-1 plays a pivotal role in different inflammatory conditions (33).…”

Section: Discussionmentioning

confidence: 99%

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Wittnam

Portelius

Zetterberg

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Wittnam

Portelius

Zetterberg

et al. 2012

Journal of Biological Chemistry

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“…32,33 The elevated expression levels of all these molecules explain the exaggerated inflammation response that characterizes septic shock. Moreover, the CD276 molecule precursor (B7-H3), which was up-modulated under LD conditions at 6 dpf, functions as both a costimulator of proinflammatory cytokine release through NFKB 34 and a co-inhibitor to control the exuberant immune responses.…”

Section: Sepsis and Tolerance To Lps In Zebrafishmentioning

confidence: 99%

The Involvement of Cholesterol in Sepsis and Tolerance to Lipopolysaccharide Highlighted by the Transcriptome Analysis of Zebrafish (Danio rerio)

Dios

Balseiro²,

Costa³

et al. 2014

Zebrafish

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Septic shock is the most common cause of death in intensive care units due to an aggressive inflammatory response that leads to multiple organ failure. However, a lipopolysaccharide (LPS) tolerance phenomenon (a nonreaction to LPS), is also often described. Neither the inflammatory response nor the tolerance is completely understood. In this work, both of these responses were analyzed using microarrays in zebrafish. Fish that were 4 or 6 days postfertilization (dpf) and received a lethal dose (LD) of LPS exhibited 100% mortality in a few days. Their transcriptome profile, even at 4 dpf, resembled the profile in humans with severe sepsis. Moreover, we selected 4-dpf fish to set up a tolerance protocol: fish treated with a nonlethal concentration of Escherichia coli LPS exhibited complete protection against the LD of LPS. Most of the main inflammatory molecules described in mammals were represented in the zebrafish microarray experiments. Additionally and focusing on this tolerance response, the use of cyclodextrins may mobilize cholesterol reservoirs to decrease mortality after a LD dose of LPS. Therefore, it is possible that the use of the whole animal could provide some clues to enhance the understanding of the inflammatory/tolerance response and to guide drug discovery.

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“…Interestingly, the oncogenic fusion protein RET/PTC expressed in PTC activates the transcription factor NF-kB and induces CCL2 gene expression (Russell et al 2003, Neely et al 2011. Recently, others and we have shown that the chemotactic activity of CCL2 depends on a modified N-terminus of the polypeptide, particularly the formation of a pyroglutamate (pE)-residue protecting against proteolytic degradation in vivo (Cynis et al 2011, Chen et al 2012. The formation of the N-terminal pE-residue is an important maturation step during synthesis and secretion of not only CCL2 but also hormones such as thyreotropin-releasing hormone and GNRH (Goren et al 1977, Abraham & Podell 1981, Awade et al 1994.…”

Section: Introductionmentioning

confidence: 99%

Role of glutaminyl cyclases in thyroid carcinomas

Kehlen¹,

Haegele²,

Menge³

et al. 2012

Endocrine-Related Cancer

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CCL2 is a chemokine known to recruit monocytes/macrophages to sites of inflammation. CCL2 is also associated with tumor progression in several cancer types. Recently, we showed that the N-terminus of CCL2 is modified to a pyroglutamate (pE)-residue by both glutaminyl cyclases (QC (QPCT)) and its isoenzyme (isoQC (QPCTL)). The pE-residue increases stability against N-terminal degradation by aminopeptidases. Here, we report an upregulation of QPCT expression in tissues of patients with thyroid carcinomas compared with goiter tissues, whereas QPCTL was not regulated. In thyroid carcinoma cell lines, QPCT gene expression correlates with the mRNA levels of its substrate CCL2. Both QPCT and CCL2 are regulated in a NF-kB-dependent pathway shown by stimulation with TNFa and IL1b as well as by inhibition with the IKK2 inhibitor and RNAi of p50. In the culture supernatant of thyroid carcinoma cells, equal amounts of pECCL2 and total CCL2 were detected by two ELISAs discriminating between total CCL2 and pECCL2, concluding that all CCL2 is secreted as pECCL2. Activation of the CCL2/CCR2 pathway by recombinant CCL2 increased tumor cell migration of FTC238 cells in scratch assays as well as thyroid carcinoma cell-derived CCL2-induced migration of monocytic THP1 cells. Suppression of CCL2 signaling by CCR2 antagonist, IKK2 inhibitor, and QPCT RNAi reduced FTC238 cell growth measured by WST8 proliferation assays. Our results reveal new evidence for a novel role of QC in thyroid carcinomas and provide an intriguing rationale for the use of QC inhibitors as a means of blocking pECCL2 formation and preventing thyroid cancer metastasis.

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

Cited by 81 publications

References 53 publications

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

The Involvement of Cholesterol in Sepsis and Tolerance to Lipopolysaccharide Highlighted by the Transcriptome Analysis of Zebrafish (Danio rerio)

Role of glutaminyl cyclases in thyroid carcinomas

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