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doi:10.22028/D291-42247
Titel: | SLPI Inhibits ATP-Mediated Maturation of IL-1β in Human Monocytic Leukocytes: A Novel Function of an Old Player |
VerfasserIn: | Zakrzewicz, Anna Richter, Katrin Zakrzewicz, Dariusz Siebers, Kathrin Damm, Jelena Agné, Alisa Hecker, Andreas McIntosh, J. Michael Chamulitrat, Walee Krasteva-Christ, Gabriela Manzini, Ivan Tikkanen, Ritva Padberg, Winfried Janciauskiene, Sabina Grau, Veronika |
Sprache: | Englisch |
Titel: | Frontiers in Immunology |
Bandnummer: | 10 |
Verlag/Plattform: | Frontiers |
Erscheinungsjahr: | 2019 |
Freie Schlagwörter: | annexin II calcium-independent phospholipase A2β caspase-1 IL-1β inflammasome SLPI nAChR P2X7 receptor |
DDC-Sachgruppe: | 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Interleukin-1β (IL-1β) is a potent, pro-inflammatory cytokine of the innate immune system that plays an essential role in host defense against infection. However, elevated circulating levels of IL-1β can cause life-threatening systemic inflammation. Hence, mechanisms controlling IL-1β maturation and release are of outstanding clinical interest. Secretory leukocyte protease inhibitor (SLPI), in addition to its well-described anti-protease function, controls the expression of several pro-inflammatory cytokines on the transcriptional level. In the present study, we tested the potential involvement of SLPI in the control of ATP-induced, inflammasome-dependent IL-1β maturation and release. We demonstrated that SLPI dose-dependently inhibits the ATP-mediated inflammasome activation and IL-1β release in human monocytic cells, without affecting the induction of pro-IL-1β mRNA by LPS. In contrast, the ATP-independent IL-1β release induced by the pore forming bacterial toxin nigericin is not impaired, and SLPI does not directly modulate the ion channel function of the human P2X7 receptor heterologously expressed in Xenopus laevis oocytes. In human monocytic U937 cells, however, SLPI efficiently inhibits ATP-induced ion-currents. Using specific inhibitors and siRNA, we demonstrate that SLPI activates the calcium-independent phospholipase A2β (iPLA2β) and leads to the release of a low molecular mass factor that mediates the inhibition of IL-1β release. Signaling involves nicotinic acetylcholine receptor subunits α7, α9, α10, and Src kinase activation and results in an inhibition of ATP-induced caspase-1 activation. In conclusion, we propose a novel anti-inflammatory mechanism induced by SLPI, which inhibits the ATP-dependent maturation and secretion of IL-1β. This novel signaling pathway might lead to development of therapies that are urgently needed for the prevention and treatment of systemic inflammation. |
DOI der Erstveröffentlichung: | 10.3389/fimmu.2019.00664 |
URL der Erstveröffentlichung: | https://doi.org/10.3389/fimmu.2019.00664 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-422472 hdl:20.500.11880/37933 http://dx.doi.org/10.22028/D291-42247 |
ISSN: | 1664-3224 |
Datum des Eintrags: | 24-Jun-2024 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary Material |
In Beziehung stehendes Objekt: | https://www.frontiersin.org/api/v3/articles/439956/file/Data_Sheet_1.PDF/439956_supplementary-materials_datasheets_1_pdf/1?isPublishedV2=false |
Fakultät: | M - Medizinische Fakultät |
Fachrichtung: | M - Anatomie und Zellbiologie |
Professur: | M - Prof. Dr. Gabriela Krasteva-Christ |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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fimmu-10-00664.pdf | 1,6 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons