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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

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