Soluble ST2 protein inhibits LPS stimulation on monocyte-derived dendritic cells

Abstract

ST2 protein is a soluble splicing variant of ST2L protein, which is the receptor for interleukin-33 (IL-33). Previously, we reported that soluble ST2 suppressed the signal transduction of lipopolysaccharide (LPS) and cytokine production in monocytic cells. To investigate whether or not this inhibitory effect occurs in dendritic cells, which are the key players in innate and adaptive immunity, human monocyte-derived dendritic cells were pre-treated with soluble ST2 protein before LPS stimulation. Although soluble ST2 did not attenuate the LPS-induced maturation of dendritic cells, pre-treatment with soluble ST2 suppressed cytokine production and inhibited LPS signaling. Moreover, the proliferation of naive T cells was inhibited significantly by soluble ST2 pre-treatment. IL-33 had little effect on the cytokine production of immature monocyte-derived dendritic cells. Furthermore, soluble ST2 protein was internalized into dendritic cells, suggesting that soluble ST2 protein acts by a noncanonical mechanism other than the sequestration of IL-33. 1 The specific receptor for IL-33 is ST2L protein, which forms a receptor complex with IL-1 receptor accessory protein. Soluble ST2 protein (sST2) is a variant of ST2L arising from alternative splicing. Because it binds with IL-33 to sequestrate the effect of IL-33, sST2 is considered an antiinflammatory factor in cases such as asthma.2 In addition, we and other groups have reported that the serum level of sST2 rises in various diseases, including asthma, autoimmune diseases, cardiovascular diseases and sepsis, although the pathological relevance of these findings remains largely unknown.

Soluble form of the ST2 gene product exhibits growth promoting activity in NIH-3T3 cells

“…Pre-treatment with IL-33 also did not influence the ST2-induced promotion of cell proliferation (data not shown) [17] . At present, it appears that ST2 itself may be responsible for the growth enhancement of NIH-3T3 cells, via an as-yet-unknown cell surface receptor for ST2 or via direct internalization as reported previously [16] . Indeed, the unexpectedly remarkable effect of shRNA-resistant ST2 ( Fig.…”

“…However, the spectrum of diseases that are accompanied by high ST2 levels in the serum and body fluids is too broad to be explained merely by immunological function(s) of the ST2 gene products. In fact, we found that ST2 suppresses colony formation of T98G glioblastoma cell line in soft agar [15] , and that the ST2 is directly internalized into dendritic cells [16] , and both these findings suggest that ST2 has a unique function other than the sequestration of IL-33 [5] .…”

The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

“…39 The soluble form of the receptor, sST2, acts as a decoy receptor blocking IL-33 signaling 25,40 and inhibiting lipopolysaccharide-induced cytokine production. 41 Previous observations in other models of inflammation have shown IL-33 to be either pro-inflammatory or anti-inflammatory depending on the disease entity. A pro-inflammatory role for IL-33 was found in respiratory syncytial virus infection, 42 and neutralizing antibodies against ST2 attenuated lung inflammation.…”

Endotoxin-Binding Peptides Derived from Casein Glycomacropeptide Inhibit Lipopolysaccharide-Stimulated Inflammatory Responses via Blockade of NF-κB activation in macrophages

“…RAW264.7 macrophages (1 × 10 6 cells) were pre-incubated with tested samples or PBS for 12 h at 37 °C following LPS stimulation (1 μg mL −1 ) for 24 h. After stimulation with LPS, the cells were washed three times with PBS and then harvested with 0.25% trypsin (Gibco, Carlsbad, CA, USA). TLR4 protein on the cell surface was analyzed by fluorescence activated cell sorting (FACS) with anti-TLR4-PE by a slight modification of previously described methods [ 27 ]. Briefly, the cells were washed three times and resuspended in FACS buffer (PBS containing 1% BSA).…”