Format

Send to

Choose Destination
J Immunol. 2015 Sep 1;195(5):2325-34. doi: 10.4049/jimmunol.1400974. Epub 2015 Jul 22.

Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release.

Author information

1
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany;
2
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany; Institute of Animal Physiology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany;
3
Protein Analytics, Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen, Germany;
4
Department of Pharmacology, Goethe University College of Pharmacy, D-60438 Frankfurt, Germany;
5
Institute for Immunology, Philipps-University Marburg, D-35043 Marburg, Germany;
6
Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany;
7
Department of Respiratory Medicine, Hannover Medical School, D-30625 Hannover, Germany;
8
Institute of Animal Physiology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany; Department of Physiology, University of Otago, Dunedin 9054, New Zealand; and.
9
Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, S-58183 Linköping, Sweden.
10
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany; Veronika.Grau@chiru.med.uni-giessen.de.

Abstract

IL-1β is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1β plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1β release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1β synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1β by caspase-1, and release of mature IL-1β. Mechanisms controlling IL-1β release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1β release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits α7, α9, and/or α10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1β and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.

PMID:
26202987
DOI:
10.4049/jimmunol.1400974
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center