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The Journal of Experimental Medicine
Year: 2009  |  Volume: 206  |  Issue: 9  |  Page No.: 1863 - 1871

TPL-2 negatively regulates interferon-{beta} production in macrophages and myeloid dendritic cells

F Kaiser, D Cook, S Papoutsopoulou, R Rajsbaum, X Wu, H. T Yang, S Grant, P Ricciardi Castagnoli, P. N Tsichlis, S. C Ley and A. O'Garra    

Abstract:

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.

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