Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8.

TitleStimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8.
Publication TypeJournal Article
Year of Publication2008
AuthorsMaelfait, J., E. Vercammen, S. Janssens, P. Schotte, M. Haegman, S. Magez, and R. Beyaert
JournalJ Exp Med
Volume205
Issue9
Pagination1967-73
Date Published2008 Sep 1
ISSN1540-9538
KeywordsAnimals, Caspase 8, Cell Line, Gene Expression Regulation, Humans, Inflammation, Interleukin-1beta, Mice, Models, Biological, RNA Interference, Signal Transduction, Toll-Like Receptor 3, Toll-Like Receptor 4
Abstract

The cytokine interleukin (IL)-1beta is a key mediator of the inflammatory response and has been implicated in the pathophysiology of acute and chronic inflammation. IL-1beta is synthesized in response to many stimuli as an inactive pro-IL-1beta precursor protein that is further processed by caspase-1 into mature IL-1beta, which is the secreted biologically active form of the cytokine. Although stimulation of membrane-bound Toll-like receptors (TLRs) up-regulates pro-IL-1beta expression, activation of caspase-1 is believed to be mainly initiated by cytosolic Nod-like receptors. In this study, we show that polyinosinic:polycytidylic acid (poly[I:C]) and lipopolysaccharide stimulation of macrophages induces pro-IL-1beta processing via a Toll/IL-1R domain-containing adaptor-inducing interferon-beta-dependent signaling pathway that is initiated by TLR3 and TLR4, respectively. Ribonucleic acid interference (RNAi)-mediated knockdown of the intracellular receptors NALP3 or MDA5 did not affect poly(I:C)-induced pro-IL-1beta processing. Surprisingly, poly(I:C)- and LPS-induced pro-IL-1beta processing still occurred in caspase-1-deficient cells. In contrast, pro-IL-1beta processing was inhibited by caspase-8 peptide inhibitors, CrmA or vFLIP expression, and caspase-8 knockdown via RNAi, indicating an essential role for caspase-8. Moreover, recombinant caspase-8 was able to cleave pro-IL-1beta in vitro at exactly the same site as caspase-1. These results implicate a novel role for caspase-8 in the production of biologically active IL-1beta in response to TLR3 and TLR4 stimulation.

DOI10.1084/jem.20071632
Alternate JournalJ. Exp. Med.
PubMed ID18725521
PubMed Central IDPMC2526192