Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells.
The observation that the T-bet transcription factor allows tissue-specific upregulation of intracellular osteopontin (Opn-i) in plasmacytoid dendritic cells (pDCs) suggests that Opn might contribute to the expression of interferon-alpha (IFN-alpha) in those cells. Here we show that Opn deficiency substantially reduced Toll-like receptor 9 (TLR9)-dependent IFN-alpha responses but spared expression of transcription factor NF-kappaB-dependent proinflammatory cytokines. Shortly after TLR9 engagement, colocalization of Opn-i and the adaptor molecule MyD88 was associated with induction of transcription factor IRF7-dependent IFN-alpha gene expression, whereas deficient expression of Opn-i was associated with defective nuclear translocation of IRF7 in pDCs. The importance of the Opn-IFN-alpha pathway was emphasized by its essential involvement in cross-presentation in vitro and in anti-herpes simplex virus 1 IFN-alpha response in vivo. The finding that Opn-i selectively coupled TLR9 signaling to expression of IFN-alpha but not to that of other proinflammatory cytokines provides new molecular insight into the biology of pDCs.
Shinohara
Mari L
ML
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Lu
Linrong
L
Bu
Jing
J
Werneck
Miriam B F
MB
Kobayashi
Koichi S
KS
Glimcher
Laurie H
LH
Cantor
Harvey
H
D000818:Animals; D002460:Cell Line; D018899:CpG Islands / Q000502:physiology; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000378:metabolism*; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000378:metabolism; D000098815:T-bet Transcription Factor
D016898:Interferon-alpha; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D053495:Osteopontin