Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines¹. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains², but the mechanisms accounting for diversification of TLR effector functions are unclear. To dissect biochemically TLR signalling, we established a system for isolating signalling complexes assembled by dimerized adaptors. Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. Using myeloid cells from TRAF3- and TRAF6-deficient mice, we show that TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. In fact, TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response.

1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine,
2. Department of Medicine, and
3. Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
4. Center for Experimental BioInformatics (CEBI), Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
5. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstr. 9, D-81675 Munich, Germany
6. †Present address: Department of Infectious Diseases, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA

Correspondence to: Hans Häcker^1,6 Correspondence and requests for materials should be addressed to H.H. (Email: Hans.Haecker@stjude.org).

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