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¹ Division of Immunoregulation and ² Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
³ Singapore Immunology Network, Biopolis, SINGAPORE 138648
⁴ Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111

CORRESPONDENCE Anne O'Garra: aogarra{at}nimr.mrc.ac.uk OR Steven C. Ley: sley{at}nimr.mrc.ac.uk

Stimulation of Toll-like receptors (TLRs) on macrophages and dendritic cells (DCs) by pathogen-derived products induces the production of cytokines, which play an important role in immune responses. Here, we investigated the role of the TPL-2 signaling pathway in TLR induction of interferon-β (IFN-β) and interleukin-10 (IL-10) in these cell types. It has previously been suggested that IFN-β and IL-10 are coordinately regulated after TLR stimulation. However, in the absence of TPL-2 signaling, lipopolysaccharide (TLR4) and CpG (TLR9) stimulation resulted in increased production of IFN-β while decreasing IL-10 production by both macrophages and myeloid DCs. In contrast, CpG induction of both IFN- and IFN-β by plasmacytoid DCs was decreased in the absence of TPL-2, although extracellular signal-regulated kinase (ERK) activation was blocked. Extracellular signal-related kinase–dependent negative regulation of IFN-β in macrophages was IL-10–independent, required protein synthesis, and was recapitulated in TPL-2–deficient myeloid DCs by retroviral transduction of the ERK-dependent transcription factor c-fos.

Abbreviations used: BMDC, BM-derived DC; BMDM, BM-derived macrophage; CHX, cycloheximide; ERK, extracellular signal-regulated kinase; IKK, IB kinase; IRF, IFN regulatory factor; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKKK, MAP-3 kinase; pDC, plasmacytoid DC; TIR, Toll/IL-1R; TLR, Toll-like receptor; TRAF, TNF receptor-associated factor; TRIF, TIR domain–containing adaptor inducing IFN-β.

© 2009 Kaiser et al.
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