Soluble ST2 Blocks Interleukin-33 Signaling in Allergic Airway Inflammation

Abstract

The ST2 gene produces a soluble secreted form and a transmembrane form, referred to as soluble ST2 and ST2L, respectively. A recent study has reported that interleukin (IL)-33 is a specific ligand of ST2L and induces production of T helper type 2 (Th2) cytokines. Although soluble ST2 is highly produced in sera of asthmatic patients and plays a critical role for production of Th2 cytokines, the function of soluble ST2 in relation to IL-33 signaling remains unclear. Here we show antagonistic effects of soluble ST2 on IL-33 signaling using a murine thymoma EL-4 cells stably expressing ST2L and a murine model of asthma. Soluble ST2 directly bound to IL-33 and suppressed activation of NF-B in EL-4 cells stably expressing ST2L, suggesting that the complex of soluble ST2 and IL-33 fails to bind to ST2L. In a murine model of asthma, pretreatment with soluble ST2 reduced production of IL-4, IL-5, and IL-13 from IL-33-stimulated splenocytes. These results indicate that soluble ST2 acts as a negative regulator of Th2 cytokine production by the IL-33 signaling. Our study provides a molecular mechanism wherein soluble ST2 modulates the biological activity of IL-33 in allergic airway inflammation.The interleukin (IL)-1 2 receptor family plays important roles in inflammatory and immunological responses. The ST2 gene is a member of the IL-1 receptor family, producing a soluble secreted form and a transmembrane form, soluble ST2 and ST2L, respectively (1-3). These proteins are generated by alternative splicing of pre-mRNA. The structure of ST2L is similar to that of IL-1 receptor type I (IL-1RI), consisting of three extracellular immunoglobulin domains and an intracellular Tollinterleukin-1 receptor domain. Although the extracellular domain is common to soluble ST2 and ST2L, soluble ST2 lacks the transmembrane and intracellular Toll-interleukin-1 receptor domains. The ST2 gene is expressed in several cells including fibroblasts and mast cells (1, 4). In particular, ST2L is preferentially expressed in murine and human Th2 cells and can be utilized as a specific marker of Th2 cells in in vitro experiments (5-8). Therefore, the function of ST2L has been suggested to correlate with Th2 cell-mediated immunological responses. However, ST2L has been an orphan receptor ever since it was first reported (5). Late in 2005, IL-33, a newly discovered member of the IL-1 cytokine family, was finally reported as a specific ligand for ST2L (9).The IL-33 gene, also described as a nuclear factor expressed in high endothelial venules (NF-HEV) (10), codes a 31-kDa protein that does not contain a signal sequence for secretion, similar to the IL-1␣, IL-1␤, and IL-18 genes (11,12). Previous study has demonstrated the processing and function of the IL-33 protein (9). The precursor 31-kDa protein (pre-IL-33) was cleaved by caspase-1 into a mature 18-kDa protein (IL-33) in in vitro experiments using a recombinant protein. Functional analysis has shown that IL-33 bound to murine mast cells expressing ST2L and stimulated the intracellular signaling pathway,...

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke

“…In a murine model of stroke, IL‐33 signaling through the membrane‐bound form of ST2 has been shown to be neuroprotective through anti‐inflammatory effects 35. In contrast, the circulating soluble form (sST2), which was measured in our study, is thought to antagonize IL‐33 signaling6 and augment neuroinflammation by operating as a decoy receptor. While our finding that sST2 is associated with HT is consistent with this hypothesis, the data remains circumstantial.…”

“…It serves as the receptor for IL‐33 and integrates inflammation, tissue fibrosis and cardiac stress 5. A soluble form (sST2) is secreted into the circulation and functions as a decoy receptor for IL‐33, inhibiting its signaling 6. Circulating levels of sST2 are associated with adverse outcome and mortality in patients with chronic heart failure (CHF) and myocardial infarction (MI) 7, 8, 9.…”

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

“…Targeting ST2L via an antibody approach 18,21 or enhancing levels of sST2 24 have both proved effective in attenuating ovalbumin-induced allergic asthma responses in Th2-biased BALB/c mice. Our targeting of ST2L alone using a novel mAb in the fungal asthma model confirmed, and also extended, these previous studies.…”

“…17 With this background, we hypothesized that the enhanced expression of ST2L during Th2-driven allergic inflammatory responses impeded the TLR9-dependent therapeutic effects of CpG in a model of fungal asthma, which was previously determined to be responsive to local (ie, lung), but not systemic, CpG therapy. 8 Although the therapeutic effects of targeting ST2L, 18 -22 increasing soluble ST2 (sST2) levels, 23,24 or targeting IL-33 25 activity in experimental asthma have been previously examined, it is not known whether the therapeutic effect of targeting IL-33/ST2L is related to enhanced TLR9 activation in this setting. In the present study, the combination of systemic CpG and an anti-ST2L monoclonal antibody (mAb) markedly reduced the severity of all features in this chronic fungal asthma model, whereas the administration of either treatment alone had no therapeutic effect at the selected doses.…”

The enigmatic processing and secretion of interleukin-33

“…14,27 IL-33 must be present extracellularly in order to play the crucial role in inflammatory, infectious and autoimmune diseases including anaphylactic shock, asthma, rheumatoid arthritis, atherosclerosis, systemic sclerosis and cardiovascular diseases. 5,11,[28][29][30][31][32][33][34][35][36][37][38] However, complexities and a number of discrepancies in the processing and secretion of IL-33 have been uncovered in the accumulated data. For example, full-length 31-kDa IL-33 1-270 has been reported, variously, as the immature/mature or inactive/active IL-33.…”