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PubMed2000

IL-10 converts human dendritic cells into macrophage-like cells with increased antibacterial activity against virulent Mycobacterium tuberculosis.

Dendritic cells (DC) are unique in their ability to initiate a primary immune response by the presentation of soluble Ags to T cells. Recent studies have shown that DC also phagocytose particulate Ags including the intracellular pathogen Mycobacterium tuberculosis. However, it is not known whether DC contain the growth of intracellular organisms or allow unlimited replication. To address this question, we infected human DC with a virulent strain of M. tuberculosis and monitored the intracellular growth. The bacteria grew two orders of magnitude within 7 days of culture. Among cytokines known to modulate mycobacterial growth particularly in murine macrophages (TNF-alpha, IFN-gamma, TGF-beta, IL-4), only IL-10 modulated the growth in human DC. This effect was specific for immature dendritic cells, as IL-10 did not induce growth inhibition in human macrophages. In searching for the mechanism of growth inhibition, we found that IL-10 induces the down-regulation of the DC marker CD1, while the macrophage marker CD14 was up-regulated. Functionally, IL-10-treated cells had a reduced capacity to induce an alloresponse, but phagocytic uptake of M. tuberculosis was more efficient. We also show that DC are inferior to macrophages in containing mycobacterial growth. These findings show that IL-10 converts DC into macrophage-like cells, thereby inducing the growth inhibition of an intracellular pathogen. At the site of a local immune response, such as a tuberculous granuloma, IL-10 might therefore participate in the composition of the cellular microenvironment by affecting the maturity and function of DC.

Anti-Bacterial Agents↗
PubMed2000

Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma.

Interleukin-15 (IL-15) induces proliferation and promotes cell survival of human T and B lymphocytes, natural killer cells, and neutrophils. Here we report the constitutive expression of a functional IL-15 receptor (IL-15R) in 6 of 6 myeloma cell lines and in CD38(high)/CD45(low )plasma cells belonging to 14 of 14 patients with multiple myeloma. Furthermore, we detected IL-15 transcripts in all 6 myeloma cell lines, and IL-15 protein in 4/6 cell lines and also in the primary plasma cells of 8/14 multiple myeloma patients. Our observations confirm the existence of an autocrine IL-15 loop and point to the potential paracrine stimulation of myeloma cells by IL-15 released from the cellular microenvironment. Blocking autocrine IL-15 in cell lines increased the rate of spontaneous apoptosis, and the degree of this effect was comparable to the pro-apoptotic effect of depleting autocrine IL-6 by antibody targeting. IL-15 was also capable of substituting for autocrine IL-6 in order to promote cell survival and vice versa. In short-term cultures of primary myeloma cells, the addition of IL-15 reduced the percentage of tumor cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowered the responsiveness to Fas-induced apoptosis and to cytotoxic treatment with vincristine and doxorubicin but not with dexamethasone. These data add IL-15 to the list of important factors promoting survival of multiple myeloma cells and demonstrate that it can be produced and be functionally active in an autocrine manner. (Blood. 2000;95:610-618)

Adult↗
PubMedDate not supplied

Collagen-receptor signaling in health and disease.

Collagens are not only essential for the mechanical resistance and resilience of multicellular organisms, but are also signaling molecules defining cellular shape and behavior. The communication between collagens and cells is achieved by cell surface receptors. Three types of cell surface receptors for collagen are known: integrins, discoidin domain receptors and glycoprotein VI. All three types independently trigger a variety of signaling pathways upon collagen-binding. Besides regulating numerous cellular responses, both integrin and discoidin domain receptors monitor the integrity of the collagenous extracellular matrix by triggering matrix degradation and renewal. Some recently discovered mechanisms of locally controlled expression of collagen, collagen-binding receptors and collagen-degrading proteases in the cellular microenvironment are described.

Collagen↗
PubMedDate not supplied

[Study of mechanisms of anti-irradiation effects of interleukin-1beta in long-term bone marrow cultures].

The influence of betaleukin (human recombinant interleukin-1 beta) on the processes of postirradiation recovery of haemopoietic precursors (GM-CFC) and the level of granulocyte-macrophag colony-stimulating factor (GM-CSF) were studied in long-term bone marrow cultures after gamma-irradiation with a dose 2 Gy. Then the betaleukin action on the contents of GM-CFC and induction of GM-CSF in the non irradiated cultures was studied. It was shown that betaleukin increased the induction of GM-CSF and raised the contents of GM-CFC in long-term bone marrow cultures, and the maximal increase of a GM-CSF level and GM-CFC amount was marked in 20 hours after introduction. At an irradiation of long-term bone marrow cultures in conditions of betaleukin introduction 20 hours prior to influence of radiation the smaller degree of damage and faster recovery of GM-CFC was observed. The data in this report suggest that one of the mechanisms of antiirradiation action of betaleukin apparently is connected to the action of the preparation on hematopoietic microenvironment cellular elements, that causes the release of a colony-stimulating factor and stimulation of recovery of haemopoietic precursors.

Animals↗
PubMed2002

Application of microarrays to the analysis of gene expression in cancer.

Molecular diagnostics is a rapidly advancing field in which insights into disease mechanisms are being elucidated by use of new gene-based biomarkers. Until recently, diagnostic and prognostic assessment of diseased tissues and tumors relied heavily on indirect indicators that permitted only general classifications into broad histologic or morphologic subtypes and did not take into account the alterations in individual gene expression. Global expression analysis using microarrays now allows for simultaneous interrogation of the expression of thousands of genes in a high-throughput fashion and offers unprecedented opportunities to obtain molecular signatures of the state of activity of diseased cells and patient samples. Microarray analysis may provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments and ultimately may lead to improved early diagnosis and innovative therapeutic approaches for cancer.

Gene Expression Profiling↗
PubMed2002

The mode of action of cytokine inhibitors.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are important mediators of inflammation and tissue damage in animal models of inflammatory arthritis and in patients with active rheumatoid arthritis (RA). Several inhibitors of these cytokines are now available for RA treatment, each having a different mode of action. Etanercept is a recombinant fusion protein of the soluble type II TNF receptor on a human IgG1 backbone, whereas infliximab is a chimeric anti-TNF-alpha monoclonal antibody containing a murine TNF-alpha binding region and human IgG1 backbone. Both agents potently and selectively bind TNF-alpha in the cellular microenvironment, thereby preventing TNF-alpha from interacting with membrane-bound TNF receptors on target cells. In comparison, anakinra is a recombinant human IL-1 receptor antagonist (IL-1Ra) that binds avidly to type 1 IL-1 receptors but does not stimulate any intracellular responses. Studies of these agents in animal models of inflammatory arthritis suggest that TNF-alpha plays a more important role in promoting inflammation, whereas IL-1 is more important in causing cartilage and bone destruction. However, these differential actions have not been borne out in clinical trials, where TNF-alpha blockers and anakinra similarly reduce clinical signs and symptoms of RA as well as slow radiographic evidence of disease progression.

Animals↗
PubMedDate not supplied

Growth factors, cytokines, chemokines and neuropeptides in the modeling of T-cells.

The T lymphocyte lineage, from initial stem cells to peripheral mature T-cells, are members of a highly reactive cell system engaged in the control of internal homoeostasis and body intactness. It fulfills its commitments in close communication with the cellular and non-cellular microenvironment and with neuroendocrine regulatory mechanisms. Tools of such communication are various substances and compounds identified as cytokines, chemokines, hormones, growth factors and neuropeptides. Any pathogenetical model of functional aberration and disease development in the T-cell system must take into account the delicate network control exerted by the above mechanisms. In the following we describe the major players in the network regulation of T-cell development and function as a basis for a computational modeling study.

Chemokines↗
PubMed2003

Carbon monoxide -- a "new" gaseous modulator of gene expression.

Carbon monoxide (CO) is an odorless, tasteless and colorless gas which is generated by heme oxygenase enzymes (HOs). HOs degrade heme releasing equimolar amounts of CO, iron and biliverdin, which is subsequently reduced to bilirubin. CO shares many properties with nitric oxide (NO), an established cellular messenger. Both CO and NO are involved in neural transmission and modulation of blood vessel function, including their relaxation and inhibition of platelet aggregation. CO, like NO, binds to heme proteins, although CO binds only ferrous (FeII) heme, whereas NO binds both ferrous and ferric (FeIII). CO enhances the activity of guanylate cyclase although it is less potent than NO. In contrast, CO inhibits other heme proteins, such as catalase or cytochrome p450. The effects of CO on gene expression can be thus varied, depending on the cellular microenvironment and the metabolic pathway being influenced. In this review the regulation of gene expression by HO/CO in the cardiovascular system is discussed. Recent data, derived also from our studies, indicate that HO/CO are significant modulators of inflammatory reactions, influencing the underlying processes such as cell proliferation and production of cytokines and growth factors.

Animals↗
PubMedDate not supplied

Growth factors, cytokines, chemokines and neuropeptides in the modeling of T cells. Part II: Data tables of normal values in man.

Members of the T lymphocyte lineage belong to a highly reactive cell system engaged in the control of internal homoeostasis and bodily intactness. It fulfills its commitments in close communication with the cellular and non-cellular microenvironment and with neuroendocrine regulatory mechanisms. The tools of such communication are various substances and compounds identified as cytokines, chemokines, hormones, growth factors, neuropeptides and components of the extracellular matrix. In a previous publication (22) we described the major players in the network regulation of T cell development and function as a basis for a computational modeling study. The present paper summarizes normal reference values for serum and/or plasma concentrations of these factors in man.

Chemokines↗
PubMed2003

Fundamental space radiobiology.

The unique feature of the space radiation environment is the dominance of high-energy charged particles (HZE or high LET radiation) emitted by the Sun and galactic sources, or trapped in the Van Allen radiation belts. These charged particles present a significant hazard to space flight crews, and accelerator-based experiments are underway to quantify the health risks due to unavoidable radiation exposure. There are three principal properties of charged particles that distinguish them from conventional radiation, i.e. gamma rays and x-rays. First, they have a defined range in matter rather than an exponential absorption profile. Second, they undergo nuclear reactions to produce secondary particles. Third, and most important, they deposit their energy along well-defined linear paths or tracks rather than diffuse fields. The structured energy deposition pattern interacts on multiple scales with the biological structures of DNA, cells and tissues to produce correlated patterns of damage that evade repair systems. Traditional concepts of dose and its associated normalization parameter, RBE (relative biological effectiveness), break down under experimental scrutiny, and probabilistic models of risk based on the number of particle traversals per cell may be more appropriate. Unique patterns of DNA damage, gene expression, mobilization of repair proteins, activation of cytokines and remodeling of cellular microenvironment are observed following exposure to high LET radiation. At low levels of exposure the communication of bioactive substances from irradiated to unirradiated "bystander" cells can amplify the damage and cause a significant deviation from linearity in dose vs. response relations. Under some circumstances, there is even a multigenerational delay in the expression of radiation-induced genetic damage (genomic instability) which is not strictly dose dependent. These issues and the experimental evidence derived from ground based experiments at particle accelerators are presented along with speculation about how modified inertial conditions might perturb homeostatic responses to radiation to further complicate risk assessment for space flight.

Animals↗
PubMed2003

Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate.

Autotaxin (ATX) is an exoenzyme that potently induces tumor cell motility, and enhances experimental metastasis and angiogenesis. ATX was shown recently to be identical to serum lysophospholipase D activity, producing lysophosphatidic acid (LPA) from lyso-glycerophospholipids. LPA, itself a strong chemoattractant for tumor cells, may mediate the actions of ATX. We now extend the substrate specificity to sphingosylphosphorylcholine (SPC), which ATX hydrolyzes to sphingosine-1-phosphate (S1P). Under migration assay conditions, this novel reaction for the production of S1P has a substrate (SPC) K(m) = 0.23 +/- 0.07 mM. In our responder cell lines (NIH3T3 clone7 and A2058), S1P exerts maximal biological effects at concentrations of 10-100 nM and is mimicked in its biological effects by ATX plus SPC. These effects include inhibition of ATX- and LPA-stimulated motility, and elevation of activated Rho. In NIH3T3 clone7 cells stimulated with platelet-derived growth factor and treated with 10-25 nM S1P, motility is not inhibited and activation of Rho is unaffected, indicating that S1P possesses specificity in its effects. The exoenzyme ATX can potentially regulate diverse processes such as motility and angiogenesis via the S1P family of receptors. Because ATX hydrolyzes nucleotides, lyso-glycerophospholipids, and phosphosphingolipids into bioactive products, it possesses the ability, depending on the availability of substrates, to act as positive or negative regulator of receptor-mediated activity in the cellular microenvironment.

3T3 Cells↗
PubMedDate not supplied

[Role of hematopoietic microenvironment in the mechanism of radioprotective action of interleukin-1 beta in long-term bone marrow cultures].

The influence of human interleukin-1 beta in different concentration on processes of postirradiation recovery of haemopoietic precursors (GM-CFC) and morphology of recognized elements of bone marrow were studied in long-term bone marrow cultures during 28 days after gamma-irradiation with a dose of 2 Gy. It was studied also the action of interleukin-1 beta on proliferation, the contents of GM-CFC and the induction of GM-CSF in non-irradiated cultures. It was shown that the injection of interleukin-1 beta increased proliferation and the content of GM-CFC and also raised an induction of GM-CSF in the non-irradiation cultures. The maximum increase of a level of GM-CSF, amount of GM-CFC and proliferation of GM-CFC was marked in 20 hours after the injection of cytokine. Under irradiation of long-term bone marrow cultures the maximum stimulation effect to recovery of GM-CFC, total number of myelocaryocytes and the content of immature and mature granulocytes were observed after the injection of interleukin-1 beta in concentration of 0.005 microgram/ml 20 hours prior to radiation exposure. The data of this report suggest that one of the mechanisms of radioprotective action of interleukin-1 beta apparently is connected with stimulation action on hematopoietic microenvironment cellular elements that causes the release of GM-CSF or/and other cytokines, and stimulation recovery of haemopoietic precursors.

Animals↗
PubMedDate not supplied

[The role of hematopoietic microenvironment in prodigiozan' mechanism of action on postradiation recovery of hemopoiesis in long-term bone marrow cultures].

Influence of prodigiozan in different concentrations on the process of postirradiation recovery of haemopoietic precursors (GM-CFC) and morphologically recognizable elements of the bone marrow were studied in long-term bone marrow cultures during 28 days after 2 Gy gamma-irradiation. Also, prodigiozan was studied for action on the contents of GM-CFC and induction of GM-CSF three, 24 and 48 hours after injection in cultures unexposed to radiation. It is shown that injection of prodigiozan in concentration 0.1-1.0 microg/ml 24 hours prior to irradiation stimulates postradiation recovery of GM-CFC number and a total number of myelocaryocytes in irradiation of long-term bone marrow cultures. In saved cultures there was an increase in the number of stromal cells 1 and 2 days after radiation. In non-exposed to radiation long-term bone marrow cultures injection of prodigiozan increased induction of GM-CSF and raised contents of GM-CFC. The maximal increase occurred 24 hours after introduction of radioprotector. It is suggested that one of the mechanisms of a radioprotective action of prodigiozan may be stimulation of hematopoietic microenvironment cellular elements leading to a marked release of GM-CSF or/and other cytokines and stimulation of recovery of hemopoietic precursors.

Animals↗
PubMedDate not supplied

Immunocytochemical detection of members of the caspase cascade of apoptosis in high-grade astrocytomas.

During the physiological process of PCD, the cell initiates a sequence of events culminating in the disintegration of the cell into small, membrane-bound apoptotic bodies. The intrinsic part of the PCD program arises from the mitochondria when it releases cytochrome c from the mitochondrial intermembrane space into the cytosol, forming the caspase-activating complex or apoptosome. The family of caspases is involved in the execution of genetically controlled PCD. Caspase-3 is expressed in normal and neoplastically transformed human cells and, like other caspases, is synthesized as an inactive, 32kDa proenzyme. Caspase-6 cleaves nuclear mitotic apparatus protein (NuMA) and mediates the shrinkage and fragmentation of cell nuclei. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis, while caspase-9 is the initiator caspase in the caspase cascade in apoptotic normal and neoplastically transformed cells. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results did in fact demonstrate the presence of high apoptotic activity within the cellular microenvironment of high-grade astrocytomas and glioblastomas. The observations identified cytoplasmic expression of caspase-3 and caspase-6 in more than 50 per cent of tumor cells, caspase-8 and caspase-9 in more than 10 per cent of tumor cells in high-grade anaplastic ASTR and glioblastoma. The immunocytochemical expression pattern in about 10 per cent of the tumor cells for caspase-3 and caspase-6 and about 1 to 5 per cent of the tumor cells for caspase-8 and caspase-9 demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that caspase-3, -6, -8 and -9 immunocytochemistry could have prognostic and immunotherapeutic significance in the treatment of these highly malignant glial tumors.

Adolescent↗
PubMed2004

Equiguard suppresses androgen-dependent LNCaP prostate cancer cell proliferation by targeting cell cycle control via down regulation of the retinoblastoma protein Rb and induction of apoptosis via the release of cytochrome c.

Lack of life-prolonging therapies has provided much of the impetus for seeking complementary and alternative management/treatment options by prostate cancer (CaP) patients. Among these, the use of dietary supplements and botanical products has been showing a sustained increase in recent years, owing in part to some encouraging pre-clinical and clinical data shown in a limited number of herbal products. Notably, however, the majority of herbal and dietary supplement products have not been rigorously studied with regard to their efficacy. In vitro mechanistic experiments are considered essential preludes and requisites to more lengthy and costly animal and human studies, in that they may provide relevant insights and scientific basis for effects some of these products purportedly might demonstrate. In vitro studies in our laboratory have shown that a polyherbal supplement, Equiguard, exhibits anti-tumor activity against hormone dependent LNCaP cells cultured in both androgen-proficient (FBS) and -deficient (CS-FBS) conditions. Clinically relevant anti-prostate cancer effects of Equiguard are vividly illustrated by growth suppression and down regulated expression of prostate specific genes, respectively, androgen receptor (AR) and prostate specific antigen (PSA). However, the mechanistic bases contributing to these effects have not been well characterized. This communication describes experiments aimed at further understanding growth arrest elicited by Equiguard in LNCaP cells cultured in FBS and CS-FBS conditions. We have focused on aspects of cell cycle control and induction of apoptosis. Regulation of cell cycle progression by Equiguard was analyzed by examining changes in the expression of Rb and cyclins D/E. Using Western blot analysis, we showed that treatment caused inhibition of Rb phosphorylation, which was accompanied by the reduction of cyclins D/E expression, in both culture conditions. Moreover, cells treated with Equiguard and cultured with FBS-supplemented media showed up-regulation of cyclin-dependent kinase inhibitor Kip1/p27. These results support the interpretation that suppression of Rb phosphorylation mediated the observed growth arrest induced by Equiguard under androgen-proficient condition. In contrast, Equiguard-treated cells cultured in CS-FBS had lowered expression of the Kip1/p27, suggesting that different control mechanisms, possibly evoked by changes in cellular microenvironments, contributed to growth suppression by Equiguard. The growth suppressive effects of Equiguard in both culture conditions were also evaluated with respect to induction of apoptosis. While Equiguard elicited apoptosis was accompanied by an increase in the level of cytosolic cytochrome c, the relative accumulation of cytochrome c in the cytosol was unaffected by culture conditions. These results suggest that the ability to trigger apoptosis as one aspect of the control of cell growth by Equiguard is integrally linked to the release of cytochrome c, by a mechanism largely independent of the presence of androgens.

Apoptosis↗
PubMedDate not supplied

Immunocytochemical detection of members of the caspase cascade of apoptosis in childhood medulloblastomas.

During the process of programmed cell death (PCD), the cell disintegrates into small, membrane-bound apoptotic bodies. Caspase-3 is ubiquitously expressed in normal and neoplastically-transformed human cells and serves as an executioner in the apoptotic or PCD pathway. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase-conjugated antigen detection technique was employed. The results demonstrated the presence of apoptotic activity within the cellular microenvironment of childhood medulloblastoma/primitive neuroectodermal tumor. The observations identified the cytoplasmic presence of caspase-3 in more than 20% of neoplastic cells. The immunocytochemical expression pattern demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells in about 5% of the tumor cells. Caspase-3 presence was also detected in the tumor infiltrating lymphocytes (TILs), representing the host's immune, mostly CD8+, cytotoxic, tumor-associated antigen (TAA)-directed effector cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that the grade and intensity of apoptosis may not only have diagnostic and prognostic significance, but could also play a leading role in the biological (fourth modality) antineoplastic treatment of these highly malignant, neuroectodermal brain tumors.

Apoptosis↗
PubMedDate not supplied

[The effect of prodigiozan on the postradiational recovery of hemopoiesis in long-term bone morrow cultures of mice of different genotypes].

The influence of prodigiozan on the processes of postirradiation recovery of hemopoiesis in long-term bone morrow cultures of two strain mice, having genetic distinctions in the condition of systems of the reparation DNA was investigated. It was showh, that the irradiation of long-term bone morrow cultures of mice reparation-defective strain 101/H resulted in the greater degree damage of early haemopoietic precursors (GM-CFC), reduction of the amount of the immature and of the mature granulocytes and of the decrease of the number of stromall cells in the comparison with the bone morrow of reparation-capable mice (CBA x C57B1)F1. Under the introduction in cultures of prodigiozan for 24 hours prior to an radiation the distinctions of the speed of postirradiation recovery of hemopoiesis substantially smoothed out, and the protective effect of the drag in bone morrow cultures of mice 101/H was comparable to those, marked in bone morrow cultures of reparation-capable strain mice (CBA x C57B1)F1. It is supposed, that this effect can be caused by the activation of the hematopoietic microenvironment cellular elements and inclusion of the mechanisms of intercellular of interactions, which provide stimulation of the regenerative processes at action radioprotective drags and can in the certain degree to compensate the defect of the systems of the reparation DNA.

Adjuvants, Immunologic↗
PubMed1991

The thymus in myasthenia gravis. Changes typical for the human disease are absent in experimental autoimmune myasthenia gravis of the Lewis rat.

In human myasthenia gravis (MG) formation of autoantibodies against acetylcholine receptor (AChR) is commonly associated with thymic changes termed lymphofollicular hyperplasia (LFH). To learn whether the thymic lesions of human MG are primary changes in the autoimmune pathogenesis, or rather secondary events caused by peripheral autoimmunization, the authors compared the pathologic changes of MG thymuses with the thymuses of Lewis rats with experimental autoimmune myasthenia gravis (EAMG). EAMG was induced either actively by immunization with AChR, or transferred passively with monoclonal antibodies (mAb) binding to AChR. The clinical diagnosis of EAMG was confirmed by electromyography. Germinal centers, which are typical for human MG thymuses, were not detectable in the thymus of EAMG rats. Scattered B cells were seen as normal components of the thymic medulla. In EAMG their number was not augmented, nor were they accumulated focally. The perivascular spaces (PVS) were not distended and the amount of reticulin was not increased. Thymic myoid cells were identified in EAMG as well as in control thymuses; their cellular microenvironment was inconspicuous. Both in normal and in EAMG thymuses, a subpopulation of myoid cells expressed the main immunogenic region of the AChR. Heavily affected rats showed a severe cortical involution, but no specific changes of the medulla. The fact that none of the thymic lesions characteristic for human MG was found in EAMG is compatible with the concept that the thymic changes in MG are primary events in the autoimmune pathogenesis of this disease.

Animals↗