A Novel Pathway Regulating Lipopolysaccharide-Induced Shock by ST2/T1 Via Inhibition of Toll-Like Receptor 4 Expression

Abstract

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-α 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-κB. Administration of sST2 in vivo after LPS challenge significantly reduced LPS-mediated mortality and serum levels of IL-6, IL-12, and TNF-α. 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.

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

“…33 Aside from its role in directing Th2-type responses, ST2L also has a well-characterized inhibitory effect on MyD88-dependent TLR activation. 17,49,50 Although TLR activation can promote Th2-type allergic inflammation, 51 targeting TLR9 with CpG has proved to be a highly effective therapeutic approach in experimental asthma. 52 The containment of Aspergillus in the allergic host requires TLR9 expression, 30 and exogenous CpG reverses fungal asthma when administered at a dose of 50 g for 2 weeks by intranasal, but not i.p., injection.…”

Elevated levels of soluble ST2 protein in dengue virus infected patients

“…Recent reports have suggested that sST2 protein could be involved in the inflammatory response as well as in Th2 immune responses [43,44]. Some evidence suggests that sST2 could act as an anti-inflammatory mediator, through a mechanism that involves the inhibition of Toll-like receptor signaling by sequestration of MyD88 and Mal adapter proteins [45,46] or inhibition of I-κB degradation [47] resulting in down-regulation of NF-κB. In vitro and in vivo experiments have shown that sST2 protein or an ST2-fusion protein is able to attenuate the production of pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-12 [30,45,48].…”

“…Some evidence suggests that sST2 could act as an anti-inflammatory mediator, through a mechanism that involves the inhibition of Toll-like receptor signaling by sequestration of MyD88 and Mal adapter proteins [45,46] or inhibition of I-κB degradation [47] resulting in down-regulation of NF-κB. In vitro and in vivo experiments have shown that sST2 protein or an ST2-fusion protein is able to attenuate the production of pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-12 [30,45,48]. In two mouse models of ischemia/reperfusion, pretreatment with an sST2-Fc fusion protein decreased the inflammatory response [49,50].…”

Expression and function of Na+/Ca2+ exchangers 1 and 3 in human macrophages and monocytes

“…Activation of NCX by Na 1 -free medium induced the release of TNF-a from macrophages comparable to that caused by LPS (1 mg/mL) used as a positive control (Fig. 8A) [47]. This occurred equally in cells maintained in Na 1 -free medium for the entire time-period (4 h) and in cells exposed to Na 1 -free medium Figure 7.…”