ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance

Brint, Elizabeth; Xu, Damo; Liu, Haiying; Dunne, Aisling; McKenzie, Andrew N. J.; O’Neill, Luke A. J.; Liew, Foo Y.

doi:10.1038/ni1050

Cited by 467 publications

(443 citation statements)

References 37 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…55 Asthmatic DCs produced significant amounts of IL-12p70 after CpG activation, but it was evident from the present study that the ST2L had an inhibitory effect on CpGmediated generation of this cytokine. Because IL-33 protein was not detected in culture supernatants of DCs, the increased presence of ST2L alone on these cells might have been sufficient to sequester the adaptor protein MyD88 17 or inhibit I B␣ degradation, 56 thereby impairing TLR signaling. These findings are consistent with the observations of Espinassous et al, 57 who showed that the exogenous addition of IL-33 enhanced lipopolysaccharide activation in macrophages, findings that mirror those we obtained from cultured asthmatic DCs (H.R.…”

Section: Discussionmentioning

confidence: 99%

“…14 -16 When activated, ST2L sequesters MyD88 adaptor protein, thereby preventing TLR-mediated signaling, including that initiated by CpG. 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.…”

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confidence: 99%

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

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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“…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].…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of soluble ST2 protein in dengue virus infected patients

et al. 2008

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Levels of the soluble form of the interleukin-1 receptor like 1 protein (IL-1RL-1 / ST2) are elevated in the serum of patients with diseases characterized by an inflammatory response. The objective of this study was to determine the concentration of soluble ST2 (sST2) in dengue infected patients during the course of the disease. Twenty four patients with confirmed dengue infection, classified as dengue fever, and eleven patients with other febrile illness (OFI) were evaluated. Levels of sST2 in serum and laboratory variables usually altered during dengue infections were measured. Dengue infected patients had higher serum sST2 levels than OFI at the end of the febrile stage and at defervescence (p=0.0088 and p=0.0004 respectively). Patients with secondary dengue infections had higher serum sST2 levels compared with patients with primary dengue infections (p=0.047 at last day of fever and p=0.030 at defervescence). Furthermore, in dengue infected patients, we found a significant negative correlation of sST2 with platelet and WBC counts, and positive correlation with thrombin time and transaminases activity. We suggest that sST2 could be a potential marker of dengue infection, could be associated with severity or could play a role in the immune response in secondary dengue virus infection.

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“…It is also possible that these two proteins function as receptor accessory proteins like AcPL. Intriguingly, a recent gene-targeting study suggested that T1/ST2 probably functions to inhibit IL-1R and TLR4 signaling (20). Although T1/ST2 cannot bind to IL-1, its TIR domain is capable of binding and probably sequestering common signaling molecules such as MyD88, preventing them from being used by IL-1R (20).…”

mentioning

confidence: 99%

Accessory Protein-Like Is Essential for IL-18-Mediated Signaling

Cheung

Chen

Cao

et al. 2005

The Journal of Immunology

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IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18Rα, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18Rα in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN-γ production. In particular, Th1 cells lacking AcPL fail to produce IFN-γ in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling.

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ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance

Cited by 467 publications

References 37 publications

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

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

Elevated levels of soluble ST2 protein in dengue virus infected patients

Accessory Protein-Like Is Essential for IL-18-Mediated Signaling

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