title: Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice.
abstract: Activation of Toll-like receptor (TLR) signaling rapidly induces the expression of inflammatory genes, which is persistent for a defined period of time. However, uncontrolled and excessive inflammation may lead to the development of diseases. 4-1BB ligand (4-1BBL) plays an essential role in sustaining the expression of inflammatory cytokines by interacting with TLRs during macrophage activation. Here, we show that inhibition of 4-1BBL signaling reduced the inflammatory responses in macrophages and ameliorated endotoxin-induced sepsis in mice. A 4-1BB-Fc fusion protein significantly reduced TNF production in macrophages by blocking the oligomerization of TLR4 and 4-1BBL. Administration of 4-1BB-Fc suppressed LPS-induced sepsis by reducing TNF production, and the coadministration of anti-TNF and 4-1BB-Fc provided better protection against LPS-induced sepsis. Taken together, these observations suggest that inhibition of the TLR/4-1BBL complex formation may be highly efficient in protecting against continued inflammation, and that 4-1BB-Fc could be a potential therapeutic target for the treatment of inflammatory diseases.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Bang
authors.forename: Sang Jick
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008262:Macrophage Activation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: 4-1BBL; Inflammation; Innate immunity; Sepsis; TNF; Toll-like receptor signaling