Inhibitory Effect of Interleukin-1α-Induced Apoptosis by Polygala Tenuifolia in Hep G2 Cells

Abstract

A human hepatoma cell line, Hep G2 cells are reliable for the study of alcohol-induced hepatotoxicity. In this study, we investigated the effect of an aqueous extract of Polygala tenuifolia Willdenow (Polygalaceae) roots (PTAE) on ethanol (EtOH)-induced cytotoxicity in Hep G2 cells. PTAE (0.01–1 μg/ml) dose-dependently inhibited the EtOH-induced interluekin-1 α (IL-1α) secretion. PTAE (0.01–1 μg/ml) also inhibited the EtOH- and IL-1α-induced cytotoxicity. Furthermore, we found that PTAE inhibited the IL-1α-induced apoptosis of Hep G2 cells. These results suggest that PTAE may prevent the EtOH-induced cytotoxicity through inhibition of the apoptosis of Hep G2 cells.     

Effect of Cysteine Protease Inhibitor Ep-475 on TNF-α-Independent Cyclophosphamide-Induced Apoptosis in Mouse Lymphosarcoma LS Cells

Cyclophosphamide 1.5–2.0-fold increased activity of cathepsins B and L in tumor tissue of mouse lymphosarcoma LS and caused tumor regression. The effect was most pronounced on day 5 after treatment. Twofold treatment with a selective cathepsin inhibitor Ep-475 slightly stimulated tumor growth in control mice and significantly reduced the antitumor effect of cyclophosphamide. Lysosomal cysteine proteases cathepsins B and L are involved, but do not play a key role in TNF--independent apoptosis in LS cells induced by cyclophosphamide.__________Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 139, No. 2, pp. 153–156, February, 2005     

Differential Sensitivity of Naïve and Memory Subsets of Human CD8+ T Cells to TNF-α-Induced Apoptosis

In this investigation, we have examined the relative sensitivity of human naïve, central memory (T_CM), and two types of effector memory CD8+ T cells (T_EM and T_EMRA) to TNF-α-induced apoptosis. Our data show that naïve and T_CM CD8+ T cells were sensitive, whereas T_EM and T_EMRA CD8+ T cells were relatively resistant to TNF-a-induced apoptosis. The apoptosis profile correlated with the activation of caspase-8 and caspase-3. However, no correlation was observed between relative sensitivity of four CD8 + T cell subsets to apoptosis and the expression of TNFR-I or TNFR-II. T_EM and T_EMRA CD8+ T cells displayed increased phosphorylation of IKKα/β and IκB and increased NF-κB activity as compared to naïve and T_CM CD8+ T cells. Bcl-2, Bcl-x_L and FLIP_L expression was higher and Bax expression was lower in T_EM and T_EMRA CD8+ T cells as compared to naïve and T_CM CD8+ T cells. These data suggest that signaling molecules downstream of TNFRs may be responsible for differential sensitivity among subsets of CD8+ T cells to TNF-α-induced apoptosis.     

Mammary Stem Cells and Breast Cancer—Role of Notch Signalling

Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44⁺/CD24⁻ and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A γ-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.     

Suppressive Effect of 19-nor-1α-25-Dihydroxyvitamin D2 on Gastric Cancer Cells and Peritoneal Metastasis Model

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits the growth of several types of human cancer cells in vitro, but its therapeutic use is limited because it causes hypercalcemia. Among its analogs, 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), has fewer calcemic effects and exhibits an activity equipotent to that of calcitriol. We assessed the antitumor and anti-inflammatory effects of paricalcitol in gastric cancer cells, and evaluated the potential role of vitamin D in the treatment of peritoneal metastatic gastric cancer. In this study, treatment with paricalcitol inhibited gastric cancer cell growth and induced cell cycle arrest. Paricalcitol also induced apoptosis and showed anti-inflammatory activity. Moreover, the growth of intraperitoneal metastases in vivo was reduced in mice treated with paricalcitol. (18)F-FDG uptake was significantly lower in the paricalcitol group compared to control group (SUV; control group 13.2 ± 5.3 vs paricalcitol group 4.5 ± 3.0). Intraperitoneal tumor volume was significantly lower in paricalcitol treated mice (control group 353.2 ± 22.9 mm(3) vs paricalcitol group 252.0 ± 8.4 mm(3)). These results suggest that the vitamin D analog, paricalcitol, has anticancer activity on gastric cancer cells by regulation of the cell cycle, apoptosis, and inflammation.     

Effects of Laminins 332 and 411 on the Epithelial—Mesenchymal Status of Colorectal Cancer Cells

Bulletin of Experimental Biology and Medicine - The effects of laminins 332 and 411 (LM-332 and LM-411) on the epithelial—mesenchymal transformation of colorectal cancer cells (lines HT-29,...     

Integrin α7 Binds Tissue Inhibitor of Metalloproteinase 3 to Suppress Growth of Prostate Cancer Cells

Integrin α7 (ITGA7) is a tumor-suppressor gene that is critical for suppressing the growth of malignant tumors; however, the mechanisms allowing ITGA7 to suppress the growth of cancer cells remain unclear. Herein, we show that ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells. The ITGA7-TIMP3 binding led to a decreased protein level of tumor necrosis factor α, cytoplasmic translocation of NF-κB, and down-regulation of cyclin D1. These changes led to an accumulation of cells in G₀/G₁ and a dramatic suppression of cell growth. Knocking down TIMP3 or ITGA7/TIMP3 binding interference largely abrogated the signaling changes induced by ITGA7, whereas a mutant ITGA7 lacking TIMP3 binding activity had no tumor-suppressor activity. Interestingly, knocking down ITGA7 ligand laminin β1 enhanced ITGA7-TIMP3 signaling and the downstream tumor-suppressor activity, suggesting the existence of a counterbalancing role between extracellular matrix and integrin signaling. As a result, this report demonstrates a novel and critical signaling mechanism of ITGA7, through the TIMP3/NF-κB/cyclin D1 pathway.Integrin α7 (ITGA7) is a member of the extracellular matrix binding proteins. As a major class of cell adhesion molecules in mammalian cells, integrins are involved in many cellular processes, including development, immune responses, leukocyte trafficking, and hemostasis.¹ The integrin superfamily consists of 24 members, each of which mediates a unique function in mammals. The regulation of integrin expression is critical for certain aspects of tissue differentiation and regeneration (eg, keratinocyte differentiation, hair follicle formation, and skeletal muscle development),^2–4 and abnormal integrin expression is associated with several human diseases (eg, muscular dystrophy, Glanzmann’s thrombasthenia, and congenital cardiac myopathy).^4–6ITGA7 forms a heterodimer with integrin β1 in the plasma membrane and is responsible for communication between the extracellular matrix and cells.⁷ Itga7-deficient mice display significant hyperplasia and hypertrophy of arteries and arterioles and a malformation of skeletal muscles.^4,8 Recent mutational analysis revealed ITGA7 mutations in prostate cancer, hepatocellular carcinoma, soft tissue leiomyosarcoma, and glioblastoma multiforme, with frequencies ranging from 25% to 83%.⁹ Many of these mutations resulted in truncation, microdeletion, or frameshift of the protein. Interestingly, patients with prostate cancer or hepatocellular carcinoma harboring ITGA7 mutations also had a higher rate of clinical relapse.A meta-analysis of previously published microarray data^10–15 indicated that ITGA7 was down-regulated in nonmetastatic prostate cancer and leiomyosarcoma, but the magnitude of the down-regulation was larger in metastatic cancers. Also, prostate cancer and soft tissue leiomyosarcoma, with focal or no ITGA7 expression, were associated with a shorter metastasis-free survival time. The forced expression of normal ITGA7 in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and cancer cell migration in vitro. A mouse model of PC3 and DU145 xenograft prostate tumors showed a dramatic reduction in tumor volume, metastatic rate, and mortality rate when ITGA7 expression was restored. However, the molecular mechanism of ITGA7-mediated tumor-suppressor activity remains unclear. Herein, we report that the tissue inhibitor of metalloproteinase 3 (TIMP3), a matrix proteinase and a tumor suppressor, interacts with the C-terminus of ITGA7. We further show that the activation of ITGA7 leads to redistribution of NF-κB to the cytoplasm, the down-regulation of cyclin D1, and cell growth arrest.     

Dysregulation of the Receptor Activator of NF-κB Ligand and Osteoprotegerin Production Influence the Apoptosis of Multiple Myeloma Patients’ Bone Marrow Stromal Cells Co-Cultured with Myeloma Cells

The interaction of multiple myeloma (MM) cells and bone marrow stromal cells (BMSCs) induces profound changes in the bone marrow environment, influencing osteoclastogenesis and MM cell survival. Differences in receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) production in BMSCs derived from MM patients and control subjects and the apoptosis of BMSCs and MM cells in co-cultures of both cell types were examined. RANKL and OPG expressions were examined by ELISA and semiquantitative RT-PCR. Apoptosis of BMSCs after contact with RPMI8226 and U266 cells was measured by flow cytometry and the level of ALP activity by the spectrophotometric method. OPG production by BMSCs was significantly inhibited after direct contact with RPMI8226 cells. Production of soluble RANKL was enhanced and the increase was more significant in the BMSCs of the MM patients than in those of the controls. In co-cultures of BMSCs and MM cells, significant apoptosis was detected with a concomitant decrease in ALP activity. This apoptosis decreased significantly in the presence of RANK-Fc, an antagonist of RANKL. Disturbances in the RANKL/OPG system are more profound in the BMSCs of MM patients than in those of control subjects after direct contact with RPMI8226 cells. Moreover, direct contact with RPMI8226 and U266 cells induces apoptosis of BMSCs which is mediated by an overproduction of RANKL.     

Role of Reactive Oxygen Species and Bcl-2 Family Proteins in TNF-α-Induced Apoptosis of Lymphocytes

We studied the in vitro apoptosis-inducing effect of recombinant TNF-α (rTNF-α) on blood lymphocytes from healthy donors. rTNF-α-induced apoptosis was accompanied by an increase in the number of cells with low mitochondrial transmembrane potential, increased intracellular content of reactive oxygen species, reduced content of Bcl-2, Bcl-xL, and Bax proteins, and elevated Bad content. The molecular mechanisms of these changes are discussed.     

Lymphocyte Subpopulations,Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-β. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-β acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-α (CD25) on CD3⁺ T cells, CD19⁺ B cells, foetal-type γδ⁺CD3⁺ T cells and foetal-type CD5⁺CD19⁺ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-β1b (BETAFERON^®, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n=8) with application of 8 Mill. units IFN-β1b every other day, and (2) placebo group (n=4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-β has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-β therapy is warranted.     

Organotypic Culture Model of Pancreatic Cancer Demonstrates that Stromal Cells Modulate E-Cadherin, β-Catenin,and Ezrin Expression in Tumor Cells

Pancreatic cancer is characterized by an intense stromal reaction. Reproducible three-dimensional in vitro systems for exploring interactions of the stroma with pancreatic cancer cells have not previously been available, prompting us to develop such a model. Cancer cells were grown on collagen/Matrigel and embedded with or without stromal cells (hTERT-immortalized human PS-1 stellate cells or MRC-5 fibroblasts) for 7 days. Proliferation and apoptosis, as well as important cell–cell adhesion and cytoskeleton-regulating proteins, were studied. PS-1 cells were confirmed as stellate based on the expression of key cytoskeletal proteins and lipid vesicles. Capan-1, and to a lesser extent PaCa-3, cells differentiated into luminal structures, exhibiting a central apoptotic core with a proliferating peripheral rim and an apico-basal polarity. Presence of either stromal cell type translocated Ezrin from apical (when stromal cells were absent) to basal aspects of cancer cells, where it was associated with invasive activity. Interestingly, the presence of ‘normal’ (not tumor-derived) stromal cells induced total tumor cell number reduction (P < 0.005) associated with a significant decrease in E-cadherin expression (P < 0.005). Conversely, β-catenin expression was up-regulated (P < 0.01) in the presence of stromal cells with predominant cytoplasmic expression. Moreover, patient samples confirmed that these data recapitulated the clinical situation. In conclusion, pancreatic organotypic culture offers a reproducible, bio-mimetic, three-dimensional in vitro model that allows examination of the interactions between stromal elements and pancreatic cancer cells.Pancreatic cancer, with a continuing dismal prognosis despite considerable progress in understanding underlying genetic and molecular events, is characterized by an intense desmoplastic stroma.^1,2,3 It is now appreciated that transformed cells interact with stromal cells, extracellular matrix proteins, and neighboring normal epithelial cells to generate feedback mechanisms essential for tumor progression.^4,5 However, few models exist to enable investigators to dissect out these interactions of cancer cells with their surrounding stroma. Recently, an excellent animal model of pancreatic cancer has been created using transgenic mice with conditional pancreatic expression of mutated K-Ras; producing tumors that mimic human pancreatic intraepithelial neoplasia and full-blown cancers.⁶ However, the long latency period involved makes this model costly and non-amenable to rapid experimental manipulation. For many of the problems needed to be investigated in pancreatic cancer it is possible that organotypic models, where cancer cells are cultured on a “synthetic” stroma comprised of an extracellular matrix gel embedded with stromal cells, can provide a solution.⁷ To our knowledge, such a three-dimensional (3D) in vitro system has not yet been developed for pancreatic cancer. Therefore we aimed to establish such a model in which we could study the effect of stromal cells (pancreatic stellate cells [PSCs] and fibroblasts) on pancreatic cancer cell behavior. We have isolated a PSC line from normal human pancreas and, additionally, have used non-tumorigenic MRC-5 fibroblasts, derived from human fetal lung, which previously were validated as representative stromal cells in the absence of a pancreatic stromal cell line.⁸ The effects of co-culture conditions on proliferation and apoptosis, as well as the expression and subcellular distribution of key proteins regulating cell–cell interactions, such as E-cadherin,⁹ β-catenin,¹⁰ and members of the Ezrin-Radixin-Moesin (ERM) family,¹¹ have been studied in pancreatic cancer cells as a means of investigating the utility of this model.We show here that reproducible quantitative data can be derived from such assays, illuminating the role and mechanisms of epithelial–stromal interactions in modulating pancreatic cancer progression.     

Pazopanib Inhibits the Activation of PDGFRβ-Expressing Astrocytes in the Brain Metastatic Microenvironment of Breast Cancer Cells

Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. p751-PDGFRβ⁺ astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ⁺ astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.Breast cancer is the second most common cause of brain metastasis after lung cancer, occurring in 10% to 15% of advanced patients and in approximately 30% of autopsies.^1,2 Risk factors for the development of brain metastases include young patient age, large primary tumors, multiple positive lymph nodes, and hormone receptor negativity.³ In addition, the incidence of brain metastasis appears to be increasing because of the introduction of more sensitive diagnostic methods and improved therapies, the latter particularly in patients with HER2-overexpressing metastatic breast cancer.⁴ The standard of care for brain metastases is palliative, and in most cases chemotherapy is ineffective.^5,6 New drugs that are both brain permeable and prevent specific pathogenic mechanisms of the brain metastasis process have been identified in preclinical experiments but await appropriate clinical trials.^7–11The cancer microenvironment is of crucial importance for a complete understanding of the disease^12–15 because it is the interface between cancer cells and pathophysiology of the patient.¹⁶ The brain represents a unique microenvironment for epithelial cancers that remains to be further investigated. Salient features include the blood-brain barrier that surrounds the vasculature and protects the brain from unwanted substances and leukocyte infiltration, and a rich cellular milieu, including neurons, pericytes, and glial cells. Because the brain is critical for both cognitive and physical function, microenvironmental changes during cancer metastasis may adversely affect the patient. A better understanding of the brain microenvironment during metastasis may contribute to development of more effective therapeutics.Relatively little is known about the microenvironment of brain metastases of breast or other cancers. Most of our information comes from experimental models of brain metastasis in which brain tropic lines are introduced into the circulation of mice via the left cardiac ventricle or carotid artery and then colonize the brain over a several-week period.^17–20 In the 231-BR model system, cancer cells extravasate the circulatory system and bind to the surrounding basement membrane through β1 integrin; in this microenvironment, cancer cells move and proliferate along the outside of the blood vessels.²¹ During the subclinical stage of the brain metastasis process, where injury is subtle but consistent, a continuous neuroinflammatory response involves activation of astrocytes and microglia, identified by expression of glial fibrillary acidic protein (GFAP) and F4/80 or CD11b/CD45, respectively.^21–23 This neuroinflammatory response is also observed in clinical samples from resected human brain metastases in which reactive astrocytes and microglia both surround and infiltrate the metastatic lesion, validating experimental observations.²² In coculture experiments, glial cells increased the number of colonies formed in soft agar by 231-BR cells by fivefold,²² and astrocytes also increased cancer cell proliferation and up-regulated the expression of survival genes,^24,25 suggesting mechanistic contributions of microenvironmental cells to brain metastasis.Consistent with what has been reported for other organs, platelet-derived growth factor (PDGF)-B is also a key protective factor in noncancerous brain damage,^26,27 contributing to blood-brain barrier stability, angiogenesis, and vascular remodeling through the activation of PDGF receptor β (PDGFRβ)-expressing brain pericytes and neuroglial progenitor cells.^28,29 During cancer progression PDGFRβ expression has long been associated with tumor-associated stromagenic and angiogenic activities.³⁰ However, its role during brain metastasis development is unknown.In this article, we characterize the neuroinflammatory microenvironment of a breast cancer experimental brain metastasis model system (231-BR cells transfected with HER2; 231-BR-HER2) and identify a novel subpopulation of metastasis-activated astrocytes that express an active (phosphorylated) form of PDGFRβ (p-PDGFRβ). The existence of this novel subset of astrocytes was confirmed in resected specimens of human brain metastasis from five patients with HER-2–overexpressing breast cancer, two patients with lung cancer, and one patient with colorectal cancer. Importantly, we demonstrate that primary cultured human astrocytes expressed (activated) p-PDGFRβ in response to tumor-derived soluble factors. We previously reported that pazopanib, an inhibitor of vascular endothelial growth factor receptors, PDGFRs, c-kit,³¹ and B-Raf^19,32 prevented brain metastasis formation in the 231-BR-HER2 model by 73%, targeting B-Raf activation in the tumor cells.¹⁹ Herein, we show that pazopanib also inhibited the activation of p-PDGFRβ–expressing astrocytes in the experimental brain metastasis model and in tumor-activated astrocytes in vitro. Our results indicate that brain-permeable drugs can target both tumor cells and the neuroinflammatory microenvironment in the brain metastatic process.     

Effect of Dehydroepiandrosterone Sulfate on Maturation and Functional Properties of Interferon-α-Induced Dendritic Cells

We studied the effect of adrenal cortex hormone dehydroepiandrosterone sulfate on maturation and functional activity of interferon-α-induced dendritic cells. Dehydroepiandrosterone sulfate stimulated differentiation and maturation of interferon-α-induced dendritic cell, which manifested in a decrease in the number of CD14⁺ cells and increase in the ratio of mature CD83⁺ dendritic cells expressing costimulatory molecules (CD80 and CD86). The induction of dendritic cell differentiation after treatment with dehydroepiandrosterone sulfate was accompanied by an increase in the production of interferon-γ. At the stage of dendritic cell maturation, the effect of dehydroepiandrosterone sulfate manifested in a 4-fold increase in tumor necrosis factor-α production. Dehydroepiandrosterone sulfate had little effect on the production of Th2/antiinfl ammatory cytokines at the stages of differentiation and maturation of interferon-α-induced dendritic cells. Dehydroepiandrosterone sulfate increased the ability of dendritic cells to stimulate Th1 cytokine production by T cells (interferon-γ). This hormone had no effect on the ability of interferon-α-induced dendritic cells to activate CD3⁺IL-4⁺T cells in mixed lymphocyte culture.     

STING Signaling in Cancer Cells: Important or Not?

Archivum Immunologiae et Therapiae Experimentalis - Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to...