ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance.
Affiliation
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.Issue Date
2010-05-15MeSH
AnimalsBacterial Proteins
Cells, Cultured
Down-Regulation
Humans
Immune Tolerance
Lipoproteins
Macrophages, Peritoneal
Mice
Mice, Inbred BALB C
Mice, Knockout
Receptors, Interleukin
Signal Transduction
Toll-Like Receptor 2
Metadata
Show full item recordCitation
ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance. 2010, 184 (10):5802-8 J. Immunol.Journal
Journal of immunology (Baltimore, Md. : 1950)DOI
10.4049/jimmunol.0904127PubMed ID
20400705Additional Links
http://www.jimmunol.org/content/184/10/5802.full.pdf+htmlAbstract
Activation of TLR signaling is critical for host innate immunity against bacterial infection. Previous studies reported that the ST2 receptor, a member of the Toll/IL-1 receptor superfamily, functions as a negative regulator of TLR4 signaling and maintains LPS tolerance. However, it is undetermined whether ST2 negatively regulates TLR2 signaling and furthermore, whether a TLR2 agonist, bacterial lipoprotein (BLP)-induced tolerance is dependent on ST2. In this study, we show that BLP stimulation-induced production of proinflammatory cytokines and immunocomplex formation of TLR2-MyD88 and MyD88-IL-1R-associated kinase (IRAK) were significantly enhanced in ST2-deficient macrophages compared with those in wild-type controls. Furthermore, overexpression of ST2 dose-dependently attenuated BLP-induced NF-kappaB activation, suggesting a negative regulatory role of ST2 in TLR2 signaling. A moderate but significantly attenuated production of TNF-alpha and IL-6 on a second BLP stimulation was observed in BLP-pretreated, ST2-deficient macrophages, which is associated with substantially reduced IRAK-1 protein expression and downregulated TLR2-MyD88 and MyD88-IRAK immunocomplex formation. ST2-deficient mice, when pretreated with a nonlethal dose of BLP, benefitted from an improved survival against a subsequent lethal BLP challenge, indicating BLP tolerance develops in the absence of the ST2 receptor. Taken together, our results demonstrate that ST2 acts as a negative regulator of TLR2 signaling, but is not required for BLP-induced tolerance.Item Type
ArticleLanguage
enISSN
1550-6606ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.0904127