Pneumologie 2018; 72(03): 225-226
DOI: 10.1055/s-0037-1615312
Infektionen
Georg Thieme Verlag KG Stuttgart · New York

SLPI inhibits ATP-mediated maturation of IL-1β from human monocytes via release of a soluble factor

A Zakrzewicz
1   Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Gießen, Gießen, Germany
,
K Siebers
1   Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Gießen, Gießen, Germany
,
S Wilker
1   Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Gießen, Gießen, Germany
,
K Richter
1   Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Gießen, Gießen, Germany
,
R Tikkanen
3   Institute of Biochemistry, Medical Faculty, Justus-Liebig-University Gießen, Gießen, Germany
,
W Padberg
1   Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Gießen, Gießen, Germany
,
S Janciauskiene
2   Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
,
V Grau
1   Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Gießen, Gießen, Germany
4   Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
07 March 2018 (online)

 
 

    Background:

    IL-1β is a potent, pro-inflammatory cytokine of the innate immune system that is crucial in host defence against infection. However, elevated systemic levels of IL-1β were described to contribute to the life-threatening systemic inflammatory response syndrome and multi organ dysfunction syndrome. Mechanisms controlling IL-1β maturation are of big clinical interest, but so far remained largely unexplored. Own preliminary experiments provided evidence that secretory leukocyte protease inhibitor (SLPI), known as a major anti-protease of the lung, can potently inhibit ATP-mediated release of IL-1β. In current studies we aimed to investigate the mechanism involved in the control of IL-1β release.

    Methods:

    LPS-primed monocytic U937 cells were stimulated with BzATP, a P2X7 receptor agonist, in the presence and absence of SLPI. IL-1β released to the medium was monitored by ELISA. Pharmacological inhibitors and siRNA technology were used to investigate the signal transduction pathway involved in the control of IL-1β release. In addition, to study the ion channel function of P2X7 receptor in the presence of SLPI, two-electrode voltage-clamp measurements were performed on oocytes overexpressing the P2X7 receptor. To determine, whether the inhibitory mechanism mediated by SLPI involves the secretion of a soluble factor, LPS-primed U937 cells were stimulated with SLPI, cell-free conditioned medium was harvested after 30 min and fractionated by ultrafiltration. The low molecular weight fraction (< 3 kDa) was tested for its inhibitory effects on the BzATP-mediated IL-1β release.

    Results:

    We demonstrated that SLPI inhibited ATP-mediated IL-1β release in a dose-dependent manner. SLPI did not directly modulate the ion channel function of the P2X7 receptor overexpressed in Xenopus laevis oocytes. Using a panel of inhibitors and siRNA, we identified the involvement of calcium-independent phospholipase A2β, Src kinase and nicotinic acetylcholine receptor subunits α7, α9 and α10 in the SLPI-mediated inhibition of IL-1β release. Moreover, we showed that this mechanism is dependent on the release of a soluble low molecular weight factor.

    Conclusions:

    We propose a novel anti-inflammatory mechanism induced by SLPI, which inhibits the ATP-dependent maturation and secretion of IL-1β. This novel signalling pathway might lead to the development of therapies urgently needed for the treatment of systemic inflammation.


    #