MRC National Institute for Medical Research, London
Science for Health
Regulating cytokine production
11 August 2009
Toll like receptors (TLR) on macrophages and dendritic cells respond to pathogen-derived products to induce the production of molecules that regulate innate and adaptive immune responses. These include the Type I interferons (IFNs), IFN-α and IFN-β, the proinflammatory cytokine interleukin-12 (IL-12), important for protective responses to infection, and interleukin-10 (IL-10), which suppresses cytokine production and prevents excessive immune response to infectious agents.
Anne O'Garra (pictured) and colleagues in NIMR's Division of Immunoregulation together with Steve Ley and colleagues in the Division of Immune Cell Biology investigated the role of the kinase TPL-2, which activates the ERK MAP kinase pathway, in regulating cytokine production by macrophages, myeloid dendritic cells and plasmacytoid dendritic cells. They show that, in the absence of TPL-2 / ERK signaling, lipopolysaccharide (TLR4) and CpG DNA (TLR9) stimulation resulted in increased production of IFN-β and IL-12, whilst decreasing IL-10 production by both macrophages and myeloid DC. In contrast, CpG induction of both IFN-α and IFN-β by plasmacytoid DC was decreased in the absence of TPL-2, although ERK activation was blocked. These results show that TPL-2 / ERK signalling has different effects on cytokine production depending on the cell type activated.
The TPL-2 MAPK signaling pathway has attracted considerable interest as a possible target for anti-inflammatory drugs because of its requirement for the production of the pro-inflammatory cytokine TNF, which has been shown to be damaging to the host in various autoimmune and inflammatory diseases. For this reason companies are developing small molecule inhibitors of TPL-2 as potential drugs to treat inflammatory diseases. However, our work suggests that TPL-2 inhibition may have undesirable pro-inflammatory effects due to its complex regulation of cytokine production. Our data, therefore, raise questions about the validity of TPL-2 as an anti-inflammatory drug target.
Anne O'Garra
Original Article
The research findings are published in full in:
Frank Kaiser, Dorthe Cook, Stamatia Papoutsopoulou, Ricardo Rajsbaum, Xuemei Wu, Huei-Ting Yang, Susan Grant, Paola Ricciardi-Castagnoli, Philip N. Tsichlis, Steven C. Ley, and Anne O´Garra (2009) TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells Journal of Experimental Medicine, epub ahead of print. Publisher abstract
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