Activated Mast Cells Produce Soluble ST2, a Decoy Receptor for IL-33

Abstract

Interleukin (IL)-33 mediates inflammatory responses in allergic and autoimmune diseases. IL-33 acts through its membrane bound receptor, ST2. A soluble spliced variant of ST2 (sST2) that lacks the ST2 cytosolic and transmembrane domains is thought to act as a decoy receptor to neutralize IL-33 activity. sST2 and IL-33 are elevated in many inflammatory diseases and serum levels of sST2 appear to correlate with disease severity. We investigated whether mast cells produce, and are a significant source of sST2. Production of sST2 and IL-33 by stimulated mast cells derived from human peripheral blood CD34+ cells and mouse bone marrow was measured by qPCR, ELISA and Western blotting. A mouse model of passive systemic anaphylaxis was used to investigate sST2 production during anaphylaxis. Antigen and IL-33 evoked substantial release of sST2 from mouse and human mast cells and did so synergistically when added together or in combination with stem cell factor, a growth factor that is critical for mast cell differentiation, growth, survival and homing. Rapid release of sST2 into circulation was also apparent during systemic anaphylaxis in mice. Human mast cells failed to generate IL-33 and IL-33 produced by mouse bone marrow-derived mast cells was retained within the cells. Mast cells are a significant source of sST2, which may serve as a modulator of exogenous IL-33 activity and, in some circumstances, serve as a possible biomarker of allergic inflammation.