A suppressive oligodeoxynucleotide expressing TTAGGG motifs modulates cellular energetics through the mTOR signaling pathway

Yazar, Volkan
Kilic, Gizem
Bulut, Ozlem
Yildirim, Tugce Canavar
Yagci, Fuat C.
Aykut, Gamze
Klinman, Dennis M.
Gürsel, Mayda
Gursel, Ihsan
Immune-mediated inflammation must be down-regulated to facilitate tissue remodeling during homeostatic restoration of an inflammatory response. Uncontrolled or over-exuberant immune activation can cause autoimmune diseases, as well as tissue destruction. A151, the archetypal example of a chemically synthesized suppressive oligodeoxynucleotide (ODN) based on repetitive telomere-derived TTAGGG sequences, was shown to successfully down-regulate a variety of immune responses. However, the degree, duration and breadth of A151-induced transcriptome alterations remain elusive. Here, we performed a comprehensive microarray analysis in combination with Ingenuity Pathway Analysis (IPA) using murine splenocytes to investigate the underlying mechanism of A151-dependent immune suppression. Our results revealed that A151 significantly down-regulates critical mammalian target of rapamycin (mTOR) activators (Pi3kcd, Pdpk1 and Rheb), elements downstream of mTOR signaling (Rps6ka1, Myc, Stat3 and Slc2a1), an important component of the mTORC2 protein complex (Rictor) and Mtor itself.The effects of A151 on mTOR signaling were doseand time-dependent. Moreover, flow cytometry and immunoblotting analyses demonstrated that A151 is able to reverse mTOR phosphorylation comparably to the well-known mTOR inhibitor rapamycin. Furthermore, Seahorse metabolic assays showed an A151 ODN-induced decrease in both oxygen consumption and glycolysis implying that a metabolically inert state in macrophages could be triggered by A151 treatment. Overall, our findings suggested novel insights into the mechanism by which the immune system is metabolically modulated by A151 ODN.


KOKSOY, C; KUZU, A; ERDEN, I; Akkaya, Ayşen (Wiley, 1995-11-01)
Catheter-related venous thrombosis is one of the most important complications of central venous catheters. The aim of this prospective study was to assess the risk factors that may be important in the development of catheter-related thrombosis. Multiple lumen (n = 20) and single lumen (n = 24) polyurethane catheters were inserted to the subclavian vein by the infraclavicular approach in 44 consecutive patients. All variables that may be significant for the development of thrombosis related to the patient, t...
Effect of suppressive DNA on CpG-induced immune activation.
Yamada, H; Gursel, I; Takeshita, F; Conover, J; Ishii, KJ; Gürsel, Mayda; Takeshita, S; Klinman, DM (The American Association of Immunologists, 2002-11-15)
Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs stimulate a strong innate immune response. This stimulation can be abrogated by either removing the CpG DNA or adding inhibitory/suppressive motifs. Suppression is dominant over stimulation and is specific for CpG-induced immune responses (having no effect on LPS- or Con A-induced activation). Individual cells noncompetitively internalize both stimulatory and suppressive ODN. Studies using ODN composed of both stimula...
MTA-1 expression is associated with metastasis and epithelial to mesenchymal transition in colorectal cancer cells
Cagatay, Seda Tuncay; Cimen, Ismail; SAVAŞ, BERNA; Banerjee, Sreeparna (Springer Science and Business Media LLC, 2013-04-01)
Although metastasis associated protein 1 (MTA1) has been widely linked to tumor metastasis, the relevant mechanisms remain to be elucidated, especially in colorectal cancer (CRC). Here, we have investigated the link between MTA1, metastasis and epithelial-mesenchymal transition (EMT) in CRC. Eighteen normal colon tissues and 91 resected tumor samples were analyzed for MTA1 expression by immunohistochemistry (IHC). IHC indicated low or no nuclear MTA1 expression in the normal tissues and significantly higher...
The expression of GST isoenzymes and p53 in non-small cell lung cancer.
Oguztßzun, Serpil; Aydin, Mehtap; Demirag, Funda; Yazici, Ulkß; Ozhavzali, Mßzeyyen; Kiliç, Murat; Can, Mesude IŠ(VM Media SP. zo.o VM Group SK, 2010-6-10)
This study investigated the immunohistochemical staining characteristics of glutathione-S-transferase alpha, pi, mu, theta and p53 in non-small cell lung carcinoma and normal lung tissue from 50 patients. The relationships between expressions of the Glutathione-S-transferase isoenzymes and some clinicopathological features were also examined. Expression of glutathione-S-transferase pi, mu, alpha, theta and p53 was assessed by immunohistochemistry for primary lung carcinomas of 50 patients from the Sanitariu...
Cutting edge: Role of toll-like receptor 9 in CpG DNA-induced activation of human cells
Takeshita, F; Leifer, CA; Gursel, I; Ishii, KJ; Takeshita, S; Gürsel, Mayda; Klinman, DM (The American Association of Immunologists, 2001-10-01)
Unmethylated CpG motifs present in bacterial DNA stimulate a rapid and robust innate immune response. Human cell lines and PBMC that recognize CpG DNA express membrane-bound human Toll-like receptor 9 (hTLR9). Cells that are not responsive to CpG DNA become responsive when transfected with hTLR9. Expression of hTLR9 dramatically increases uptake of CpG (but not control) DNA into endocytic vesicles. Upon cell stimulation, hTLR9 and CpG DNA are found in the same endocytic vesicles. Cells expressing hTLR9 are ...
Citation Formats
V. Yazar et al., “A suppressive oligodeoxynucleotide expressing TTAGGG motifs modulates cellular energetics through the mTOR signaling pathway,” INTERNATIONAL IMMUNOLOGY, pp. 39–48, 2020, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/47038.