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*
Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom; and
Department of Cell and Molecular Biology, AstraZeneca Lund, Lund, Sweden
ST2/ST2L, a member of the IL-1R gene family, is expressed by
fibroblasts, mast cells, and Th2, but not Th1, cells. It exists in both
membrane-bound (ST2L) and soluble forms (ST2). Although ST2L has
immunoregulatory properties, its ligand, cellular targets, and mode of
action remain unclear. Using a soluble ST2-human IgG fusion
protein, we demonstrated that ST2 bound to primary bone marrow-derived
macrophages (BMM) and that this binding was enhanced by treatment with
LPS. The sST2 treatment of BMMs inhibited production of the LPS-induced
proinflammatory cytokines IL-6, IL-12, and TNF-
but did not alter
IL-10 or NO production. Treatment of BMMs with sST2 down-regulated
expression of Toll-like receptors-4 and -1 but induced nuclear
translocation of NF-
B. Administration of sST2 in vivo after LPS
challenge significantly reduced LPS-mediated mortality and serum levels
of IL-6, IL-12, and TNF-. Conversely, blockade of endogenous ST2
through administration of anti-ST2 Ab exacerbated the toxic
effects of LPS. Thus, ST2 has anti-inflammatory properties that act
directly on macrophages. We demonstrate here a novel regulatory pathway
for LPS-induced shock via the ST2-Toll-like receptor 4 route. This may
be of considerable therapeutic potential for reducing the severity and
pathology of inflammatory diseases.
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