scholarly journals Continuing Effect of Cytokines and Toll-Like Receptor Agonists on Indoleamine-2,3-Dioxygenase-1 in Human Periodontal Ligament Stem/Stromal Cells

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2696
Author(s):  
Christian Behm ◽  
Alice Blufstein ◽  
Johannes Gahn ◽  
Barbara Kubin ◽  
Andreas Moritz ◽  
...  
Keyword(s):  
Protein Expression ◽  
Enzymatic Activity ◽  
Stromal Cells ◽  
Periodontal Ligament ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tnf Α ◽  
Inflammatory Stimuli ◽  
Ifn Γ

Transplanted mesenchymal stem/stromal cells (MSCs) are a promising and innovative approach in regenerative medicine. Their regenerative potential is partly based upon their immunomodulatory activities. One of the most investigated immunomediators in MSCs, such as in periodontal ligament-derived MSCs (hPDLSCs), is indoleamine-2,3-dioxygenase-1 (IDO-1) which is upregulated by inflammatory stimuli, like cytokines. However, there are no data concerning continuing IDO-1 expression in hPDLSCs after the removal of inflammatory stimuli, such as cytokines and toll-like receptor (TLR) agonist-2 and TLR-3. Hence, primary hPDLSCs were stimulated with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, TLR-2 agonist Pam3CSK4 or TLR-3 agonist Poly I/C. IDO-1 gene and protein expression and its enzymatic activity were measured up to five days after removing any stimuli. IL-1β- and TNF-α-induced IDO-1 expression and enzymatic activity decreased in a time-dependent manner after cessation of stimulation. IFN-γ caused a long-lasting effect on IDO-1 up to five days after removing IFN-γ. Both, TLR-2 and TLR-3 agonists induced a significant increase in IDO-1 gene expression, but only TLR-3 agonist induced significantly higher IDO-1 protein expression and enzymatic activity in conditioned media (CM). IDO-1 activity of Poly I/C- and Pam3CSK4-treated hPDLSCs was higher at one day after removal of stimuli than immediately after stimulation and declined to basal levels after five days. Among all tested stimuli, only IFN-γ was able to induce long-lasting IDO-1 expression and activity in hPDLSCs. The high plasticity of IDO-1 expression and its enzymatic activity in hPDLSCs due to the variable cytokine and virulence factor milieu and the temporal-dependent responsiveness of hPDLSCs may cause a highly dynamic potential of hPDLSCs to modulate immune responses in periodontal tissues.

scholarly journals miR-221 suppresses ICAM-1 translation and regulates interferon-γ-induced ICAM-1 expression in human cholangiocytes

2010 ◽  
Vol 298 (4) ◽  
pp. G542-G550 ◽  
Author(s):  
Guoku Hu ◽  
Ai-Yu Gong ◽  
Jun Liu ◽  
Rui Zhou ◽  
Caishu Deng ◽  
...  
Keyword(s):  
Protein Expression ◽  
Posttranscriptional Regulation ◽  
Untranslated Region ◽  
Inflammatory Responses ◽  
Target Prediction ◽  
Interferon Γ ◽  
Pathological Feature ◽  
Dependent Manner ◽  
Inflammatory Stimuli ◽  
Ifn Γ

Aberrant cholangiocyte reactions in response to inflammatory stimuli are important pathogenic factors for the persistent biliary inflammation in patients with cholangiopathies. Overexpression of intercellular cell adhesion molecule-1 (ICAM-1) in cholangiocytes is a common pathological feature in inflammatory cholangiopathies and can promote cholangiocyte interactions with effector lymphocytes in the portal region. In this study, we tested the involvement of miRNA-mediated posttranscriptional regulation in IFN-γ-induced ICAM-1 expression in cholangiocytes. Using both immortalized and nonimmortalized human cholangiocyte cell lines, we found that IFN-γ activated ICAM-1 transcription and increased ICAM-1 protein expression. Inhibition of ICAM-1 transcription could only partially block IFN-γ-induced ICAM-1 expression at the protein level. In silico target prediction analysis revealed complementarity of miR-221 to the 3′-untranslated region of ICAM-1 mRNA. Targeting of ICAM-1 3′-untranslated region by miR-221 resulted in translational repression in cholangiocytes but not ICAM-1 mRNA degradation. Functional inhibition of miR-221 with anti-miR-221 induced ICAM-1 protein expression. Moreover, IFN-γ stimulation decreased miR-221 expression in cholangiocytes in a signal transducer and activator of transcription 1-dependent manner. Transfection of miR-221 precursor abolished IFN-γ-stimulated ICAM-1 protein expression. In addition, miR-221-mediated expression of ICAM-1 on cholangiocytes showed a significant influence on the adherence of cocultured T cells. These findings indicate that both transcriptional and miRNA-mediated posttranscriptional mechanisms are involved in IFN-γ-induced ICAM-1 expression in human cholangiocytes, suggesting an important role for miRNAs in the regulation of cholangiocyte inflammatory responses.

IFN-γ, Unlike TNF-α, LPS, or CD40 Signal, Is Required and Sufficient To Induce Indoleamine 2,3-Dioxygenase Activity in Mesenchymal Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2311-2311
Author(s):  
Karin Tarte ◽  
Delphine Monnier ◽  
Patricia Ame-Thomas ◽  
Joelle Dulong ◽  
Céline Bonnaventure ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Dependent Manner ◽  
Clinical Grade ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Immunological Properties ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tnf Α ◽  
Ifn Γ

Abstract In addition to their extensive proliferation and differentiation potential, adult bone-marrow derived mesenchymal stem cells (MSC) have been recently demonstrated to display non-HLA restricted immunosuppressive capacities in vitro. Accordingly, preliminary clinical trials have begun using MSC for prevention or treatment of acute graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation setting. However, very few conclusive data are currently available concerning i) the mechanisms of MSC-mediated immunomodulation, ii) the migration and engraftment of infused MSC, and iii) the influence of cellular environment and soluble factors on their outcome and immunological properties, especially in the context of GVHD-associated inflammation. Using a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), we first confirmed the major implication of this enzyme in the MSC-dependent inhibition of PBMC and purified T cell alloantigen-induced proliferation. Such results were extended to clinical-grade MSC generated in a large scale closed culture system in the presence of clinical-grade fetal calf serum and basic fibroblast growth factor. In addition, MSC exerted the same dose-response anti-proliferative effect either they were third-party or autologous to MLR-responder cells and irradiated or non-irradiated. We could not point out in this system a role for PGE2, despite the use of two well-known inhibitors, or for membrane and soluble HLA-G molecules. Moreover, we shown that IFN-γ was sufficient to trigger, in a dose-dependent manner, the simultaneous induction of IDO expression, at the mRNA and protein levels, and IDO activity, evaluated through the measurement of tryptophan/kynurenine ratio by HPLC. On the contrary, purified peripheral blood monocytes constitutively expressed an inactive form of IDO, and IFN-γ operated only at posttranscriptionnal level in these cells. Antagonist anti-IFN-γ MoAb blocked the induction of IDO activity induced on MSC by allogeneic MLR supernatant, suggesting that IFN-γ is absolutely required for induction of IDO in MSC during immune response. TNF-α and LPS also modulated MSC immune functions through induction of a complex set of genes, such as those coding for CXCL9, CXCL10, and CCL5 inflammatory chemokines involved in GVHD. However, they could not induce IDO activity. CD40 marker was always detected at the beginning of clinical-grade MSC culture. It was lost after several passages but remained inducible by IFN-γ and TNF-α. Treatment of MSC by trimeric CD40L induced expression of several genes involved in immune reaction, such as BAFF, but not CD80 and CD86 costimulatory molecules or IDO. In conclusion, IDO is an essential factor for immunosuppressive properties of clinical-grade MSC. Inflammatory cytokines, LPS, and contact with activated CD40Lpos T cells could markedly alter immunological properties of MSC. Such modifications must be taken into account for their further use as immunomodulator treatments in GVHD context.

scholarly journals Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

2007 ◽  
Vol 81 (18) ◽  
pp. 9838-9850 ◽  
Author(s):  
Hyeon-Sook Suh ◽  
Meng-Liang Zhao ◽  
Mark Rivieccio ◽  
Shinyeop Choi ◽  
Erin Connolly ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Expression ◽  
Interleukin 1 ◽  
T Cell Response ◽  
Poly I:C ◽  
Dependent Manner ◽  
Hiv Encephalitis ◽  
Indoleamine 2,3 Dioxygenase ◽  
Ifn Γ ◽  
Tlr3 Ligand Poly

ABSTRACT Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism and has been implicated in neurotoxicity and suppression of the antiviral T-cell response in HIV encephalitis (HIVE). Here we show that the Toll-like receptor 3 (TLR3) ligand poly(I:C) (PIC) induces the expression of IDO in human astrocytes. PIC was less potent than gamma interferon (IFN-γ) but more potent than IFN-β in inducing IDO. PIC induction of IDO was mediated in part by IFN-β but not IFN-γ, and both NF-κB and interferon regulatory factor 3 (IRF3) were required. PIC also upregulated TLR3, thereby augmenting the primary (IFN-β) and secondary (IDO and viperin) response genes upon subsequent stimulation with PIC. In HIVE, the transcripts for TLR3, IFN-β, IDO, and viperin were increased and IDO immunoreactivity was detected in reactive astrocytes as well as macrophages and microglia. PIC caused suppression of intracellular replication of human immunodeficiency virus pseudotyped with vesicular stomatitis virus G protein and human cytomegalovirus in a manner dependent on IRF3 and IDO. The involvement of IDO was demonstrated by partial but significant reversal of the PIC-mediated antiviral effect by IDO RNA interference and/or tryptophan supplementation. Importantly, the cytokine interleukin-1 abolished IFN-γ-induced IDO enzyme activity in a nitric oxide-dependent manner without suppressing protein expression. Our results demonstrate that IDO is an innate antiviral protein induced by double-stranded RNA and suggest a therapeutic utility for PIC in human viral infections. They also show that IDO activity can be dissociated from protein expression, indicating that the local central nervous system cytokine and nitric oxide environment determines IDO function.

scholarly journals Upregulation of Cytokines Is Detected in the Placentas of Cattle Infected with Neospora caninum and Is More Marked Early in Gestation When Fetal Death Is Observed

2008 ◽  
Vol 76 (6) ◽  
pp. 2352-2361 ◽  
Author(s):  
Anne Rosbottom ◽  
E. Helen Gibney ◽  
Catherine S. Guy ◽  
Anja Kipar ◽  
Robert F. Smith ◽  
...  
Keyword(s):  
Protein Expression ◽  
Fetal Death ◽  
Neospora Caninum ◽  
Late Gestation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Cytokine Mrna ◽  
Early Gestation ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT The protozoan parasite Neospora caninum causes fetal death after experimental infection of pregnant cattle in early gestation, but the fetus survives a similar infection in late gestation. An increase in Th1-type cytokines in the placenta in response to the presence of the parasite has been implicated as a contributory factor to fetal death due to immune-mediated pathological alterations. We measured, using real-time reverse transcription-PCR and enzyme-linked immunosorbent assay, the levels of cytokines in the placentas of cattle experimentally infected with N. caninum in early and late gestation. After infection in early gestation, fetal death occurred, and the levels of mRNA of both Th1 and Th2 cytokines, including interleukin-2 (IL-2), gamma interferon (IFN-γ), IL-12p40, tumor necrosis factor alpha (TNF-α), IL-18, IL-10, and IL-4, were significantly (P < 0.01) increased by up to 1,000-fold. There was extensive placental necrosis and a corresponding infiltration of CD4+ T cells and macrophages. IFN-γ protein expression was also highly increased, and a modest increase in transforming growth factor β was detected. A much smaller increase in the same cytokines and IFN-γ protein expression, with minimal placental necrosis and inflammatory infiltration, occurred after N. caninum infection in late gestation when the fetuses survived. Comparison of cytokine mRNA levels in separated maternal and fetal placental tissue that showed maternal tissue was the major source of all cytokine mRNA except for IL-10 and TNF-α, which were similar in both maternal and fetal tissues. These results suggest that the magnitude of the cytokine response correlates with but is not necessarily the cause of fetal death and demonstrate that a polarized Th1 response was not evident in the placentas of N. caninum-infected cattle.

scholarly journals Tanshinone IIA Attenuates Chronic PancreatitisInduced Pain in Rats via Downregulation of HMGB1 and TRL4 Expression in the Spinal Cord

2015 ◽  
Vol 18;4 (4;18) ◽  
pp. E615-E628
Author(s):  
Lei Chen
Keyword(s):  
Chronic Pancreatitis ◽  
Western Blot ◽  
Proinflammatory Cytokine ◽  
Mechanical Allodynia ◽  
Tanshinone Iia ◽  
Trinitrobenzene Sulfonic Acid ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Tnf Α ◽  
Dose Dependent

Background: Chronic pancreatitis (CP) is a long-standing inflammation of the exocrine pancreas, which typically results in severe and constant abdominal pain. Previous studies on the mechanisms underlying CP-induced pain have primarily focused on the peripheral nociceptive system. A role for a central mechanism in the mediation or modulation of abdominal pain is largely unknown. Tanshinone IIA (TSN IIA), an active component of the traditional Chinese medicine Danshen, exhibits anti-inflammatory properties via downregulation of the expression of high-mobility group protein B1 (HMGB1), a late proinflammatory cytokine. HMGB1 binds and activates toll-like receptor 4 (TLR4) to induce spinal astrocyte activation and proinflammatory cytokine release in neuropathic pain. Objective: In this study, we investigated the effect of TSN IIA on pain responses in rats with trinitrobenzene sulfonic acid (TNBS)-induced CP. The roles of central mechanisms in the mediation or modulation of CP were also investigated. Study Design: A randomized, double-blind, placebo-controlled animal trial. Methods: CP was induced in rats by intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). Pancreatic histopathological changes were characterized with semi-quantitative scores. The abdomen nociceptive behaviors were assessed with von Frey filaments. The effects of intraperitoneally administered TSN IIA on CP-induced mechanical allodynia were tested. The spinal protein expression of HMGB1 was determined by western blot. The spinal mRNA and protein expression of proinflammatory cytokines IL-1β, TNF-α, and IL-6 were determined by RT-PCR and western blot, respectively. The spinal expression of the HMGB1 receptor TRL4 and the astrocyte activation marker glial fibrillary acidic protein (GFAP) were determined by western blot or immunohistological staining after intraperitoneal injection of TSN IIA or intrathecal administration of a neutralizing anti-HMGB1 antibody. Results: TNBS infusion resulted in pancreatic histopathological changes of chronic pancreatitis and mechanical allodynia in rats. TSN IIA significantly attenuated TNBS-induced mechanical allodynia in a dose-dependent manner. TNBS significantly increased the spinal expression of HMGB1 and proinflammatory cytokines IL-1β, TNF-α, and IL-6. These TNBS-induced changes were significantly inhibited by TSN IIA in a dose-dependent manner. Furthermore, TSN IIA, but not the neutralizing anti-HMGB1 antibody, significantly inhibited TNBS-induced spinal TLR4 and GFAP expression. Limitations: In addition to TLR4, HMGB1 can also bind to toll-like receptor-2 (TLR2) and the receptor for advanced glycation end products (RAGE). Additional studies are warranted to ascertain whether HMGB1 contributes to CP-induced pain through activation of these receptors. Conclusions: Our results suggest that spinal HMGB1 contributes to the development of CPinduced pain and can potentially be a therapeutic target. TSN IIA attenuates CP-induced pain via downregulation of spinal HMGB1 and TRL4 expression. Therefore, TSN IIA may be a potential anti-nociceptive drug for the treatment of CP-induced pain. Key words: Chronic pancreatitis, HMGB1, proinflammatory cytokine, Tanshinone IIA, spinal cord, astrocyte, TLR4

scholarly journals Therapeutic effect and mechanism of action of quercetin in a rat model of osteoarthritis

2019 ◽  
Vol 48 (3) ◽  
pp. 030006051987346 ◽  
Author(s):  
Jun Zhang ◽  
Jing Yin ◽  
Daohong Zhao ◽  
Chaoran Wang ◽  
Yuhao Zhang ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Mechanism Of Action ◽  
Rat Model ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Tnf Α ◽  
Dose Dependent ◽  
Light Chain Enhancer ◽  
Necrosis Factor

Objective To study the therapeutic effect and mechanism of action of quercetin in a rat model of osteoarthritis (OA). Methods The OA rat model was established by intra-articular injection of papain. Changes in knee diameter, toe volume and histopathology were measured. Levels of interleukin (IL)-β and tumor necrosis factor (TNF)-α were assessed by ELISA. Relative expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was evaluated by western blotting. Results Compared with rats treated with papain alone, changes in knee diameter, toe volume and Makin' s score were less apparent in OA rats treated with quercetin. Levels of serum IL-1β and TNF-α were also reduced in quercetin-treated OA rats. Expression of TLR-4 and NF-κB was significantly suppressed in a dose-dependent manner in quercetin-treated OA rats. Conclusion Quercetin exhibited a therapeutic effect in OA rats, which may be related to inhibition of IL-1β and TNF-α production via the TLR-4/NF-κB pathway.

scholarly journals Effects of bone marrow-derived mesenchymal stromal cells on gene expression in human alveolar type II cells exposed to TNF-α , IL-1β , and IFN-γ

2018 ◽  
Vol 6 (16) ◽  
pp. e13831 ◽  
Author(s):  
Matthew Schwede ◽  
Erin M. Wilfong ◽  
Rachel L. Zemans ◽  
Patty J. Lee ◽  
Claudia dos Santos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

2001 ◽  
Vol 69 (4) ◽  
pp. 2025-2030 ◽  
Author(s):  
Shuhua Yang ◽  
Shunji Sugawara ◽  
Toshihiko Monodane ◽  
Masahiro Nishijima ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Lipid A ◽  
Micrococcus Luteus ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Monocytic Cells ◽  
Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

Toll-like receptor 3 agonist enhances IFN-γ and TNF-α production by murine uterine NK cells

2007 ◽  
Vol 7 (5) ◽  
pp. 588-596 ◽  
Author(s):  
Jianhong Zhang ◽  
Rui Sun ◽  
Haiming Wei ◽  
Dongmei Wu ◽  
Zhigang Tian
Keyword(s):  
Nk Cells ◽  
Toll Like Receptor ◽  
Tnf Α ◽  
Ifn Γ ◽  
Uterine Nk Cells
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