Cutting Edge: Role of Toll-Like Receptor 9 in CpG DNA-Induced Activation of Human Cells

Takeshita, Fumihiko; Leifer, Cynthia A.; Gürsel, İhsan; Ishii, Ken J.; Takeshita, Saoko; Gürsel, Mayda; Klinman, Dennis M.

doi:10.4049/jimmunol.167.7.3555

Cited by 520 publications

(385 citation statements)

References 21 publications

Supporting

Mentioning

370

Contrasting

Unclassified

Order By: Relevance

“…This suggests that TLR9 is not sufficient for transducing the A/D-type CpG DNA signal, and that another molecule(s) cooperatively functions to induce IFN-␣ production with TLR9. It is assumed that oligodeoxynucleotides are incorporated into cells through a pathway not requiring any specific sequences and that only CpG DNAs can bind to TLR9 and trigger TLR9 signaling in the endosome (10,28). However, confocal microscopic analysis revealed that conventional and A/D-CpG DNAs are destined for different cell compartments (29).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

Hemmi

Kaisho

Takeda

et al. 2003

The Journal of Immunology

305

208

View full text Add to dashboard Cite

Oligodeoxynucleotides containing unmethylated CpG motifs (CpG DNAs) can function as powerful immune adjuvants by activating APC. Compared with conventional phosphorothioate-backbone CpG DNAs, another type of CpG DNAs, called an A or D type (A/D-type), possesses higher ability to induce IFN-α production. Conventional CpG DNAs can exert their activity through Toll-like receptor 9 (TLR9) signaling, which depends on a cytoplasmic adapter, MyD88. However, it remains unknown how A/D-type CpG DNAs exhibit their immunostimulatory function. In this study we have investigated murine dendritic cell (DC) responses to these two distinct CpG DNAs. Not only splenic, but also in vitro bone marrow-derived, DCs could produce larger amounts of IFN-α in response to A/D-type CpG DNAs compared with conventional CpG DNAs. This IFN-α production was mainly due to the B220+ DC subset. On the other hand, the B220− DC subset responded similarly to both CpG DNAs in terms of costimulatory molecule up-regulation and IL-12 induction. IFN-α, but not IL-12, induction was dependent on type I IFN. However, all activities of both CpG DNAs were abolished in TLR9- and MyD88-, but were retained in DNA-PKcs-deficient DCs. This study demonstrates that the TLR9-MyD88 signaling pathway is essential for all DC responses to both types of CpG DNAs.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In addition, TLR9 expression is sufficient to confer responsiveness to CpG DNA on a human kidney cell line (9,10). Some CpG DNAs can activate human immune cells more efficiently than murine ones, while others can activate murine cells more effectively than human ones.…”

mentioning

confidence: 91%

The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

Hemmi

Kaisho

Takeda

et al. 2003

The Journal of Immunology

305

208

View full text Add to dashboard Cite

show abstract

“…TLR9 recognizes viral CpG sequences and induces the induction of IFN-a (Takeshita et al, 2001;Lund et al, 2003;Krug et al, 2004). However, as membrane restriction prevents TLRs from sampling the cytosol where much of the viral life cycle occurs, cytosolic PRRs provide comprehensive innate immune recognition.…”

Section: Viral Recognitionmentioning

confidence: 99%

NF-κB and the immune response

2006

View full text Add to dashboard Cite

“…10) Next we examined Fgf23 expression in BMDCs treated with Pam3CSK4 and CpG-ODN, which are known ligands for TLR2 and TLR9, respectively. 10,13,14) Treatment with 0.5 µg/mL Pam3CSK4 significantly increased Fgf23 expression in BMDCs. Fgf23 expression in BMDCs treated with 1 µM CpG-ODN was slightly increased by about 1.7 times but not significantly (Fig.…”

Section: Fig 2 Expression Of Fgf23 In Immune Tissues and Cells (A) mentioning

confidence: 99%

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Masuda

Ohta

Morita

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-κB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes.Key words fibroblast growth factor (Fgf); Fgf23; macrophage; dendritic cell; inflammationThe fibroblast growth factors (Fgfs) family consists of 22 polypeptide growth factors that are widely expressed in developing and adult tissues and regulate diverse biological processes, including angiogenesis, mitogenesis, cellular differentiation, and tissue repair. 1,2) Fgfs can be classified into three groups, canonical, intracellular, and hormone-like Fgfs. The canonical Fgfs bind to and activate Fgf receptors (Fgfrs) on the cell surface, resulting in the activation of several cytoplasmic signal transduction pathways. These canonical Fgfs function in a paracrine manner. The intracellular Fgfs act as intracellular signaling molecules in an Fgfr-independent manner. Hormone-like Fgfs, including Fgf15/19, Fgf21, and Fgf23, depends on Fgfrs to elicit biological responses, although they potentially function in an endocrine manner. 3) One of these hormone-like Fgfs, Fgf23, was originally identified in mice and humans by a DNA database search and was a well-known physiological regulator of phosphate and vitamin D metabolisms. [3][4][5][6] Fgf23 is produced by osteoblasts/osteocytes in response to 1,25-dihydroxyvitamine D, the biologically active form of vitamin D. 3,5,6) Secreted Fgf23 increases urinary phosphate excretion by reducing luminal expression of sodium-phosphate co-transporters in the proximal tubule. Secreted Fgf23 also attenuates systemic levels of 1,25-dihydroxyvitamine D, which stimulates phosphate...

show abstract

Cutting Edge: Role of Toll-Like Receptor 9 in CpG DNA-Induced Activation of Human Cells

Cited by 520 publications

References 21 publications

The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

NF-κB and the immune response

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Contact Info

Product

Resources

About