TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells.
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-beta (IFN-beta) and interleukin-10 (IL-10) in these cell types. It has previously been suggested that IFN-beta 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-beta while decreasing IL-10 production by both macrophages and myeloid DCs. In contrast, CpG induction of both IFN-alpha and IFN-beta 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-beta 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.
Kaiser
Frank
F
Division of Immunoregulation, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Cook
Dorthe
D
Papoutsopoulou
Stamatia
S
Rajsbaum
Ricardo
R
Wu
Xuemei
X
Yang
Huei-Ting
HT
Grant
Susan
S
Ricciardi-Castagnoli
Paola
P
Tsichlis
Philip N
PN
Ley
Steven C
SC
O'Garra
Anne
A
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D015151:Immunoblotting; D016899:Interferon-beta / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D017931:DNA Primers; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D016753:Interleukin-10; D016899:Interferon-beta; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse