scholarly journals Crocetin Activates Foxp3 Through TIPE2 in Asthma-Associated Treg Cells

2015 ◽  
Vol 37 (6) ◽  
pp. 2425-2433 ◽  
Author(s):  
Jurong Ding ◽  
Jianhua Su ◽  
Li Zhang ◽  
Jian Ma
Keyword(s):  
Flow Cytometry ◽  
Tumor Necrosis ◽  
Chinese Herb ◽  
Treg Cells ◽  
The Other ◽  
Tnf Alpha ◽  
Mouse Lung ◽  
Treatment Results ◽  
Underlying Mechanisms ◽  
Necrosis Factor

Background/Aims: Regulatory T cells (Treg) are critical regulators of asthma. Crocetin is isolated from Chinese herb saffron and is a natural carotenoid dicarboxylic acid with anti-inflammatory potential. However, the effects of Crocetin on asthma as well as the underlying mechanisms have not been studied. Methods: We used Crocetin to treat mice with established ovalbumin (OVA)-induced asthma. We purified CD4+CD25+ Treg cells by flow cytometry and analyzed the levels of two immunoregulatory proteins Foxp3 and tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) in Treg cells. We depleted either Foxp3 or TIPE2 in mouse lung through lentivirus-mediated delivery of shRNA, and analyzed their effects on severity of asthma and Treg cells after Crocetin treatment. Results: Crocetin treatment significantly reduced the severity of an ovalbumin (OVA)-induced asthma in mice. Moreover, Crocetin significantly increased the levels of TIPE2 and Foxp3 in Treg cells and the number of Treg cells. Depletion of Foxp3 abolished the increased in Treg cells, and the effects of Crocetin on the severity of asthma, without affecting TIPE2 levels in Treg cells. On the other hand, depletion of TIPE2 abolished both the increased in Treg cells and the effects of Crocetin on the severity of asthma, through suppressing Foxp3. Conclusion: Crocetin may activate Foxp3 through TIPE2 in asthma-associated Treg cells to mitigate the severity of asthma.

scholarly journals The role of apoptosis-inducing receptors of the tumor necrosis factor family in thyroid cancer

2003 ◽  
Vol 178 (2) ◽  
pp. 205-216 ◽  
Author(s):  
CS Mitsiades ◽  
V Poulaki ◽  
N Mitsiades
Keyword(s):  
Thyroid Cancer ◽  
Tumor Necrosis Factor ◽  
Thyroid Carcinoma ◽  
Tumor Necrosis ◽  
Fas Ligand ◽  
Carcinoma Cells ◽  
The Other ◽  
Tnf Alpha ◽  
Other Hand ◽  
Necrosis Factor

The tumor necrosis factor (TNF) family comprises several ligands, such as the prototype TNF-alpha, the Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), which trigger apoptosis in susceptible cells by activating respective cell-surface receptors. The study of these cell death pathways has attracted significant attention in several fields, including that of thyroid cancer, because they participate in immune system function, as an arm of cell-mediated cytotoxicity, and because recombinant ligands are available for pharmacological use. TNF-alpha is a pluripotent cytokine that induces both pro-apoptotic and anti-apoptotic effects on thyroid carcinoma cells. FasL triggers apoptosis in other tumor types, but thyroid carcinoma cells are resistant to this effect. On the other hand, TRAIL potently and selectively kills thyroid carcinoma cells. Consequently, TRAIL is the only member of the family with significant anticancer activity and an acceptable toxicity profile to be used as a novel therapy for thyroid cancer. The caspase inhibitor FLIP plays a significant role in negatively regulating receptor-induced apoptosis. Thelper 1-type cytokines, such as interferon-gamma, TNF-alpha and interleukin-1beta increase the sensitivity of both normal and neoplastic thyrocytes to FasL and TRAIL. On the other hand, IGF-I and other growth/survival factors produced in the local tumor microenvironment activate the phosphatidylinositol 3-kinase/Akt kinase pathway and exert an anti-apoptotic effect by upregulating several apoptosis inhibitors, including FLIP. Pharmacological modulation of apoptosis induced by FasL and TRAIL/Apo2L holds promise of therapeutic applications in human malignancies.

The in vivo immunomodulatory effects of recombinant interferon gamma plus recombinant tumor necrosis factor-alfa.

1991 ◽  
Vol 9 (10) ◽  
pp. 1831-1839 ◽  
Author(s):  
W J Urba ◽  
W C Kopp ◽  
J W Clark ◽  
J W Smith ◽  
R G Steis ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Interferon Gamma ◽  
Intramuscular Injection ◽  
Tumor Necrosis ◽  
The Other ◽  
Tnf Alpha ◽  
Simultaneous Administration ◽  
Ifn Gamma ◽  
Necrosis Factor

We conducted a phase I study in which an intramuscular injection of interferon gamma (IFN gamma) at 10, 50, or 100 micrograms/m2 was followed 5 minutes later by an intramuscular injection of 10, 50, or 100 micrograms/m2 of tumor necrosis factor-alfa (TNF alpha) at another site every other day for 20 days (10 doses). The addition of TNF alpha to IFN gamma reduced both the magnitude and duration of IFN gamma-mediated effects on peripheral blood monocyte expression of Fc receptors (FcRs) and HLA-DR and production of hydrogen peroxide. This inhibition was related to the dose of TNF alpha. On the other hand, TNF alpha and IFN gamma appeared to have an additive stimulatory effect on the production of neopterin by monocytes. The highest serum levels of neopterin were detected in patients who received the highest doses of both IFN gamma and TNF alpha. Thus, conflicting conclusions regarding the effect of the combination on immune activation are possible. If the activation of peripheral blood monocytes is the appropriate surrogate measure of the immune enhancement of the combination, then the simultaneous administration of IFN gamma and TNF alpha is ineffective, and future attempts to exploit the potential additive or synergistic effects of this combination of cytokines in humans may need to explore sequential administration schemata. On the other hand, if serum neopterin levels are a more reliable index of immune activation, simultaneous administration of 100 micrograms/m2 IFN gamma and 50 micrograms/m2 TNF alpha every other day (the maximally tolerated dose [MTD]) should be used in phase II testing. This dilemma points out the limitations of currently available methods of human immune assessment and the inadequacies in our capacity to gauge what particular immune measure or set of measures predict for in vivo antitumor effects.

scholarly journals Tumor necrosis factor (TNF)-induced protein phosphorylation in a human rhabdomyosarcoma cell line is mediated by 60-kD TNF receptors (TR60)

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2211-2220 ◽  
Author(s):  
A Mire-Sluis ◽  
A Meager
Keyword(s):  
Tumor Necrosis Factor ◽  
Protein Phosphorylation ◽  
Cell Line ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Tnf Receptors ◽  
Protein Kinase C Inhibitors ◽  
Rhabdomyosarcoma Cell Line ◽  
Rhabdomyosarcoma Cell ◽  
Necrosis Factor

Abstract In the present study, we used a cloned derivative, KYM-1D4, of the human rhabdomyosarcoma cell line, KYM-1, known to express high numbers of the two tumor necrosis factor (TNF) receptors, TR60 and TR80, and to be highly sensitive to TNF alpha-mediated cytotoxicity/antiproliferation, to investigate the role of TR60 and TR80 in protein phosphorylation. Using permeabilized KYM-1D4 cells, it was found that TNF alpha strongly induced phosphorylation of proteins of molecular weight 80, 65, 58, 42, and 30 kD. Addition of a monoclonal antibody (MoAb) against TR60 was shown to induce cytotoxicity/antiproliferation in KYM-1D4 cells and the same pattern of protein phosphorylation as TNF alpha, whereas addition of an MoAb against TR80 was both noncytotoxic and ineffective in inducing protein phosphorylation. In contrast, in a highly TNF alpha-resistant KYM-1- derived cell line, 37B8R, no protein phosphorylation was induced with either TNF alpha or the agonistic anti-TR60 MoAb. However, when 37B8R was allowed to revert to partial TNF sensitivity by culture in the absence of TNF alpha, the resultant cell line, 37B8S, was found to regain inducibility of protein phosphorylation by TNF alpha. These results indicate that expression of functional TR60 in KYM-1-related cell lines is principally involved in TNF-mediated cytotoxicity/antiproliferation and is necessary for the induction of protein phosphorylation. Nevertheless, the latter, although apparently strongly associated with cytotoxicity, was probably involved in protective mechanisms because protein kinase C inhibitors that inhibited TNF alpha and anti-TR60-induced phosphorylation increased the cytotoxic/antiproliferative response to these mediators.

Tumor necrosis factor-alpha inhibits lipid and lipoprotein transport by Caco-2 cells

1995 ◽  
Vol 269 (6) ◽  
pp. G953-G960 ◽  
Author(s):  
M. Mehran ◽  
E. Seidman ◽  
R. Marchand ◽  
C. Gurbindo ◽  
E. Levy
Keyword(s):  
Lipid Metabolism ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Low Density Lipoproteins ◽  
Tnf Alpha ◽  
Low Density ◽  
Necrosis Factor Alpha ◽  
Apo B ◽  
Factor Alpha ◽  
Necrosis Factor

Cytokines, important mediators of inflammation, have been shown to cause disturbances in circulating and hepatic lipid metabolism. Although the intestine plays a major role in dietary fat transport and largely contributes to plasma lipoproteins, the effects of cytokines on intestinal lipid handling remain unknown. In the present study, the modulation of lipid, apoprotein, and lipoprotein synthesis and secretion by tumor necrosis factor-alpha (TNF-alpha) was investigated in Caco-2 cells. Highly differentiated and polarized cells (20 days in culture) were incubated for 20 h with recombinant human TNF-alpha (100-500 ng/ml). No cytotoxic effect of TNF-alpha cells was observed, as indicated by the determinations of Caco-2 cell viability and monolayer transepithelial resistance. Moreover, no differences in cell maturation (sucrase activity) or cell proliferation ([3H]thymidine incorporation and cell cycle analysis) were detected between treated and control cultures. Significant inhibition of lipid secretion by TNF-alpha was observed, with the greatest reduction at 500 ng/ml. TNF-alpha significantly decreased Caco-2 cell secretion of phospholipids (22%), triglycerides (30%), and cholesteryl ester (37%). It also significantly diminished the export of newly synthesized low-density lipoproteins (LDL; 20%) and high-density lipoproteins (HDL; 13%), with a lesser effect on very low-density lipoproteins (VLDL; 3%). The lipid composition of these lipoproteins was minimally affected. De novo synthesis of apo A-I, apo B-100, and apo B-48 was also markedly reduced by TNF-alpha. Sphingomyelinase activity was not increased and cell content of sphingomyelin was not altered, suggesting that inhibitory effects on lipid and apoprotein of TNF-alpha were not mediated by the ceramide pathway. Our results indicate that TNF-alpha may play a role in modulating intestinal lipid metabolism, thus affecting circulating lipoproteins.

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