Inhibition of 4‐1BBL‐regulated TLR response in macrophages ameliorates endotoxin‐induced sepsis in mice. Issue 3 (21st January 2015)

• Record Type: Journal Article
• Authors: Bang, Bo Ram; Kim, Sang Jick; Yagita, Hideo; Croft, Michael; Kang, Young Jun
• Is Part Of: European journal of immunology. Volume 45:Issue 3(2015:Mar.)
• Page Start: 886
• Page End: 892
• Publication Date: 2015-01-21
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201445174
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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.</p> </abstract>