Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum.

2.50
Hdl Handle:
http://hdl.handle.net/10033/346155
Title:
Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum.
Authors:
Scherer, Olga; Steinmetz, Heinrich; Kaether, Christoph; Weinigel, Christina; Barz, Dagmar; Kleinert, Hartmut; Menche, Dirk; Müller, Rolf; Pergola, Carlo; Werz, Oliver
Abstract:
The macrolide archazolid inhibits vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, and potently suppresses cancer cell growth at low nanomolar concentrations. In view of the growing link between inflammation and cancer, we investigated whether inhibition of V-ATPase by archazolid may affect primary human monocytes that can promote cancer by sustaining inflammation through the release of tumor-promoting cytokines. Human primary monocytes express V-ATPase, and archazolid (10-100nM) increases the vesicular pH in these cells. Archazolid (10nM) markedly reduced the release of pro-inflammatory (TNF-α, interleukin-6 and -8) but also of anti-inflammatory (interleukin-10) cytokines in monocytes stimulated with LPS, without affecting cell viability up to 1000nM. Of interest, secretion of interleukin-1β was increased by archazolid. Comparable effects were obtained by the V-ATPase inhibitors bafilomycin and apicularen. The phosphorylation of p38 MAPK and ERK-1/2, Akt, SAPK/JNK or of the inhibitor of NFκB (IκBα) as well as mRNA expression of IL-8 were not altered by archazolid in LPS-stimulated monocytes. Instead, archazolid caused endoplasmic reticulum (ER) stress response visualized by increased BiP expression and accumulation of IL-8 (and TNF-α) at the ER, indicating a perturbation of protein secretion. In conclusion, by interference with V-ATPase, archazolid significantly affects the secretion of cytokines due to accumulation at the ER which might be of relevance when using these agents for cancer therapy.
Affiliation:
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.
Citation:
Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum. 2014, 91 (4):490-500 Biochem. Pharmacol.
Journal:
Biochemical pharmacology
Issue Date:
15-Oct-2014
URI:
http://hdl.handle.net/10033/346155
DOI:
10.1016/j.bcp.2014.07.028
PubMed ID:
25107704
Type:
Article
Language:
en
ISSN:
1873-2968
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorScherer, Olgaen
dc.contributor.authorSteinmetz, Heinrichen
dc.contributor.authorKaether, Christophen
dc.contributor.authorWeinigel, Christinaen
dc.contributor.authorBarz, Dagmaren
dc.contributor.authorKleinert, Hartmuten
dc.contributor.authorMenche, Dirken
dc.contributor.authorMüller, Rolfen
dc.contributor.authorPergola, Carloen
dc.contributor.authorWerz, Oliveren
dc.date.accessioned2015-03-04T13:31:11Zen
dc.date.available2015-03-04T13:31:11Zen
dc.date.issued2014-10-15en
dc.identifier.citationTargeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum. 2014, 91 (4):490-500 Biochem. Pharmacol.en
dc.identifier.issn1873-2968en
dc.identifier.pmid25107704en
dc.identifier.doi10.1016/j.bcp.2014.07.028en
dc.identifier.urihttp://hdl.handle.net/10033/346155en
dc.description.abstractThe macrolide archazolid inhibits vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, and potently suppresses cancer cell growth at low nanomolar concentrations. In view of the growing link between inflammation and cancer, we investigated whether inhibition of V-ATPase by archazolid may affect primary human monocytes that can promote cancer by sustaining inflammation through the release of tumor-promoting cytokines. Human primary monocytes express V-ATPase, and archazolid (10-100nM) increases the vesicular pH in these cells. Archazolid (10nM) markedly reduced the release of pro-inflammatory (TNF-α, interleukin-6 and -8) but also of anti-inflammatory (interleukin-10) cytokines in monocytes stimulated with LPS, without affecting cell viability up to 1000nM. Of interest, secretion of interleukin-1β was increased by archazolid. Comparable effects were obtained by the V-ATPase inhibitors bafilomycin and apicularen. The phosphorylation of p38 MAPK and ERK-1/2, Akt, SAPK/JNK or of the inhibitor of NFκB (IκBα) as well as mRNA expression of IL-8 were not altered by archazolid in LPS-stimulated monocytes. Instead, archazolid caused endoplasmic reticulum (ER) stress response visualized by increased BiP expression and accumulation of IL-8 (and TNF-α) at the ER, indicating a perturbation of protein secretion. In conclusion, by interference with V-ATPase, archazolid significantly affects the secretion of cytokines due to accumulation at the ER which might be of relevance when using these agents for cancer therapy.en
dc.language.isoenen
dc.subject.meshBase Sequenceen
dc.subject.meshCell Lineen
dc.subject.meshCytokinesen
dc.subject.meshDNA Primersen
dc.subject.meshDose-Response Relationship, Drugen
dc.subject.meshEndoplasmic Reticulumen
dc.subject.meshHumansen
dc.subject.meshMacrolidesen
dc.subject.meshMicroscopy, Fluorescenceen
dc.subject.meshMonocytesen
dc.subject.meshPhosphorylationen
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen
dc.subject.meshSignal Transductionen
dc.subject.meshVacuolar Proton-Translocating ATPasesen
dc.titleTargeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.en
dc.identifier.journalBiochemical pharmacologyen

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