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Results for “tissue microenvironment”

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PubMed1997

Relaxin and breast cancer.

Relaxin is a peptide hormone of luteal origin with a broad range of biological activities on tissues and organs of the female reproductive system as well as on other targets not directly related to the reproductive function. The mammary gland is one of the major targets for relaxin, which has been shown to promote growth and differentiation of mammary parenchyma and stroma. Based on the recognition of the mammotrophic action of relaxin, further research could show that this peptide also influences the behaviour of breast cancer cells in vitro. In fact, when relaxin was added to the culture medium of MCF-7 breast adenocarcinoma cells for short exposure times it had a biphasic effect on their growth, stimulating cell proliferation at low, nanomolar concentrations and inhibiting it at high, micromolar concentrations. In the longer times, relaxin had a marked growth-inhibitory effect on MCF-7 cells at any concentration assayed, and concurrently promoted cell differentiation and expression of adhesion molecules which are known to binder the spreading ability of cancer cells. The positive effect of relaxin on MCF-7 cell differentiation was even enhanced when these cells were cocultured with myoepithelial cells, thus recreating a microenvironment reminiscent of the tissue architecture of the mammary ducts in vivo. Concerning the mechanisms of action of relaxin on MCF-7 cells, it seems that the growth-inhibiting and differentiation-promoting effects of the peptide are mediated through the activation of the synthetic pathway of nitric oxide.

Adenocarcinoma↗

PubMed2000

Fates of human B-cell precursors.

Development of mammalian B-lineage cells is characterized by progression through a series of checkpoints defined primarily by rearrangement and expression of immunoglobulin genes. Progression through these checkpoints is also influenced by stromal cells in the microenvironment of the primary tissues wherein B-cell development occurs, ie, fetal liver and bone marrow and adult bone marrow. This review focuses on the developmental biology of human bone marrow B-lineage cells, including perturbations that contribute to the origin and evolution of B-lineage acute lymphoblastic leukemia and primary immunodeficiency diseases characterized by agammaglobulinemia. Recently described in vitro and in vivo models that support development and expansion of human B-lineage cells through multiple checkpoints provide new tools for identifying the bone marrow stromal cell-derived molecules necessary for survival and proliferation. Mutations in genes encoding subunits of the pre-B cell receptor and molecules involved in pre-B cell receptor signaling culminate in X-linked and non-X-linked agammaglobulinemia. A cardinal feature of these immunodeficiencies is an apparent apoptotic sensitivity of B-lineage cells at the pro-B to pre-B transition. On the other end of the spectrum is the apoptotic resistance that accompanies the development of B-lineage acute lymphoblastic leukemia, potentially a reflection of genetic abnormalities that subvert normal apoptotic programs. The triad of laboratory models that mimic the bone marrow microenvironment, immunodeficiency diseases with specific defects in B-cell development, and B-lineage acute lymphoblastic leukemia can now be integrated to deepen our understanding of human B-cell development.

Adult↗

PubMed1997

Somatic transgene immunization with DNA encoding an immunoglobulin heavy chain.

A plasmid DNA containing a chimeric immunoglobulin heavy-chain gene with tissue-specific promoter and enhancer elements was used as a model system to study the events triggered by a single intraspleen DNA inoculation in adult C57Bl/6 mice. A single intraspleen inoculation was followed in a week by secretion of transgene immunoglobulins and production of immunoglobulin M (IgM) anti-immunoglobulins. Their kinetics of serum appearance were almost superimposable. While anti-immunoglobulin antibodies remained detectable for over 6 months, transgene immunoglobulins disappeared after 3-4 weeks. However, transgene mRNA was detected in the spleen for 4 months. A multiplex polymerase chain reaction (PCR) analysis on splenic genomic DNA 17 days after inoculation demonstrated that the transgene was integrated in the host chromosomal DNA. The nucleotide sequence of the rearranged VDJ region from splenic genomic DNA was identical to that of the parental plasmid DNA, hence ruling out that hypermutation had occurred. A booster injection of immunoglobulin encoded by the transgene on day 200 elicited a typical secondary immune response with IgG1 and IgG2b antibodies. These results demonstrate that a single inoculation of an immunoglobulin heavy-chain DNA targeted to spleen lymphocytes leads to spontaneous integration of the transgene into the host DNA, and that this is sufficient to initiate immunity and establish immunologic memory. Our data also show that minute amounts (<100 ng/ml) of an endogenously produced protein secreted in the microenvironment of a lymphoid tissue generate immunity and establish immunologic memory rather than tolerance.

Animals↗

PubMed1986

Presence of interferon in venous blood draining from gut-associated lymphoid tissue.

The question has been examined of whether interferon (IFN), produced in the microenvironment of the gut-associated lymphoid tissue (GALT) during the physiological response, is consumed locally, or whether some spills over and is drained into the general circulation. Plasma IFN levels were measured in venous blood draining from abdominal organs that are normally in contact with exogenous and endogenous interferon inducers. The results obtained from three rodent species indicate the presence of a venous-arterial and GALT venous-peripheral venous gradient, suggesting that at least some of the IFN produced in the GALT and spleen is absorbed via blood capillaries and detectable in the regional vessels. Owing to the rapid turnover of IFN, arterial or peripheral venous blood showed a basal level. The antiviral activity (AA) in rat and mouse blood appears to be attributable to IFN-gamma.

Animals↗

PubMed2006

Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection.

The organized structure of lymphatic tissues (LTs) constitutes a microenvironment referred to as a niche that plays a critical role in immune system homeostasis by promoting cellular interactions and providing access to cytokines and growth factors on which cells are dependent for survival, proliferation, and differentiation. In chronic human immunodeficiency virus type 1 (HIV-1) infection, immune activation and inflammation result in collagen deposition and disruption of this LT niche. We have previously shown that these fibrotic changes correlate with a reduction in the size of the total population of CD4+ T cells. We now show that this reduction is most substantial within the naïve CD4+ T-cell population and is in proportion to the extent of LT collagen deposition in HIV-1 infection. Thus, the previously documented depletion of naïve CD4+ T cells in LTs in HIV-1 infection may be a consequence not only of a decreased supply of thymic emigrants or chronic immune activation but also of the decreased ability of those cells to survive in a scarred LT niche. We speculate that LT collagen deposition might therefore limit repopulation of naïve CD4+ T cells with highly active antiretroviral therapy, and thus, additional treatments directed to limiting or reversing inflammatory damage to the LT niche could potentially improve immune reconstitution.

Adult↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed2005

Hypoxia suppresses the production of matrix metalloproteinases and the migration of human monocyte-derived dendritic cells.

As most solid tumors are hypoxic, dendritic cells (DC) in solid tumors are also exposed to hypoxia. While many adaptation responses of tumor cells to hypoxia are known, it is yet to be determined how hypoxia affects the functions of DC. To explore the effects of hypoxia on the functions of DC, we compared the expression of surface markers, cytokines, chemokine receptors and matrix metalloproteinases (MMP) of human monocyte-derived DC (hmDC) differentiated under hypoxia to those differentiated under normoxia. Both groups of hmDC expressed similar levels of surface markers and cytokines. However, expression of MMP-9 and membrane type-1-MMP, as well as migrating activity, was significantly suppressed in hmDC differentiated under hypoxia compared with their normoxia counterparts. We also demonstrated that trichostatin A restored the production of MMP-9 in hmDC, under hypoxia. Collectively, our findings show that a hypoxic microenvironment suppresses the production of MMP in hmDC, most probably through the deacetylation of promoter regions of MMP, thus suppressing the migrating activity of hmDC. Our results suggest that the hypoxic microenvironment in solid tumor tissues may suppress the function of DC.

Biomarkers↗

PubMed1993

Gene expression screening for specific genes associated with mouse mammary tumor development.

The preneoplastic hyperplastic alveolar nodule is a frequent and well-characterized precursor to mammary tumors in the mouse. Although the biological characteristics of the preneoplastic state have been understood for many years, the molecular alterations associated with preneoplasia and tumorigenicity are unknown. We applied the technique of differential display of mRNA to two closely matched cell populations of mammary preneoplasias that differed only in their tumorigenic potential. Two mRNAs were isolated that were overexpressed only in tumorigenic preneoplasias and in tumors and not in normal pregnant mammary gland or in nontumorigenic preneoplasias. Partial nucleotide sequencing indicated that one of the mRNAs had not yet been described, whereas the second mRNA was highly homologous to a relatively uncharacteristic gene termed pT-2. These results illustrate the utility of the differential display method for isolating and identifying uniquely expressed genes from tissues maintained in the microenvironment where tumors arise naturally.

Animals↗

PubMed1990

The architecture of bone marrow cell populations.

Marrow is a loosely bound tissue in which hemopoiesis has frequently been considered to be randomly distributed. The case is presented, however, for an organized and structured marrow in which close relationships exist between hemopoietic tissue and a regulatory microenvironment. Distributions of myeloid cells in the mouse femur are described, and a dynamic picture of their movement, with differentiation and maturation from the endosteal surface of the bone to their release via the central venous sinus, is painted. It is also shown that this structure is established within three weeks of birth. By contrast, mature lymphoid cells (but not their progenitors) are uniformly distributed. Regulatory stromal elements in the marrow are also structured and their localization is found to correspond closely to the properties of the progenitor populations. Such structure has potential practical importance, particularly in the field of medical, industrial or accidental radiation exposure where bone may introduce non-uniform dose distributions in the marrow.

Animals↗

PubMed2000

Multipotency of a bone marrow stromal cell line, TBR31-2, established from ts-SV40 T antigen gene transgenic mice.

Bone marrow is believed to contain multipotential stromal stem cells which can differentiate into osteoblasts, chondrocytes, adipocytes, and myoblasts (Prockop, D. J. Science 276, 71-74, 1997). Therefore, characterization and identification of the stem-like cell within the stromal cells are important to understand bone marrow function in relation to the hematopoietic microenvironment, and repair/regeneration of tissue defects. TBR31-2 cell, a bone marrow stromal cell line established from bone marrow of transgenic mice harboring temperature-sensitive (ts) simian virus (SV) 40T-antigen gene for immortality, is induced toward both adipocytic and osteogenic cells under conditions of the inactivation of T-antigen (Okuyama, R., Yanai, N., Obinata, M. Exp. Cell Res. 218, 424-429, 1995). In this work, using a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, mRNA expressions of tissue-specific differentiation markers for adipocyte (lipoprotein lipase), osteoblast (type I collagen and osteocalcin), chondrocyte (type II and X collagen), and muscle cell (desmin) were examined during a long-term culture of the cell. In addition, histochemical studies showed the appearance of adipocytic, osteoblastic, chondrocytic, and muscle cells during this long-term culture. Thus, TBR31-2, which has characteristics of an undifferentiated cell, has the potential to express the multipotential cell lineages. These results indicated that a multipotential progenitor cell including potential to differentiate into a muscle cell and which is situated in the mesenchymal cell lineage was first obtained.

Animals↗

PubMed2002

The role of cytokines in the epithelial cancer microenvironment.

The epithelial tumour microenvironment is a complex tissue comprising variable numbers of tumour cells, fibroblasts, endothelial cells and infiltrating leucocytes. Cytokines are key molecules controlling autocrine or paracrine communications within and between these individual cell types. Under some circumstances, endogenous cytokines may orchestrate host responses against the tumour, but there is increasing evidence that the cytokine network contributes to tumour growth, progression and host immuno-suppression. In this review we outline some of the actions of endogenous cytokines in epithelial tumours with particular emphasis on tumour necrosis factor alpha, TNF, related inflammatory cytokines and the chemokine group of chemoattractant cytokines.

Animals↗

PubMed1993

Adhesion molecules in cell interactions.

During a successful immune response, several families of adhesion molecules participate in a cascade of binding events that lead to the binding of leukocytes, both to each other and to cell types such as the endothelium and epithelium. A central theme emerging from recent studies is that the function of an adhesion receptor cannot be inferred from its expression alone; rather, adhesion receptors are 'selected' to perform distinct effector functions based on their cell-background and factors present in the local microenvironment. Thus, adhesion receptors expressed on different cell-types may find themselves in different states of 'activation-readiness' and may be further selected by prevailing conditions in the microenvironment to bind tissue-specific ligands and mediate leukocyte effector functions such as homing or transendothelial migration.

Animals↗

PubMed2004

Regulation of activities of NK cells and CD4 expression in T cells by human HNP-1, -2, and -3.

Human neutrophil defensin alpha (HNP) is a group of cationic peptides of diverse physiological roles. Recent studies revealed the nature of HNPs as the dominant HLA-DR binding peptides on malignant cancer cells, which may block the major histocompatibility complex for antigen presentation. Here we show that HNPs may inhibit T cells by downregulating CD4 expression, a molecule of critical importance for T cell's interaction with the target cell. HNPs also inhibited tumor-cell-lysis activities of NK cells by downregulating CD16-CD56 expression. More importantly, HNPs were markedly elevated in 14 cancer tissues out of 15 self-paired human colorectal cancers and their adjacent noncancerous tissues. The subset compositions of HNPs extracted from cancer tissues and neutrophils were identical. Immunohistochemical studies indicated that HNPs mainly distributed in the infiltrated neutrophils in the interstitium. The elevated HNPs in cancer tissues may create a microenvironment unfavorable for adaptive immune reaction, implicating the cancer evasion.

CD4 Antigens↗

PubMed2005

Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function.

The lymphotoxin axis is important for the maintenance of several specialized lymphoid microenvironments in secondary lymphoid tissue. Lymphoid-tissue architecture is highly plastic and requires continual homeostatic signaling to maintain its basal functional state. The cellularity of lymph nodes in adult mice was reduced by systemic blockade of lymphotoxin-beta receptor (LTbeta R) signaling with a soluble decoy receptor both in resting and reactive settings. This reduction in cellularity resulted from greatly impaired lymphocyte entry into lymph nodes due to decreased levels of peripheral lymph node addressing (PNAd) and MAdCAM on high endothelial venules (HEV). LTbeta R signaling was required to maintain normal levels of RNA expression of MAdCAM, and also of PNAd by regulating the expression of key enzymes and scaffold proteins required for its assembly. Thus, the homeostatic maintenance of functional HEV status in adult mice relies largely on LTbeta R signaling.

Animals↗

PubMed2006

The transport of manganese across the blood-brain barrier.

The mammalian central nervous system (CNS) possesses a unique and specialized capillary adaptation, referred to as the blood-brain barrier (BBB). The BBB maintains an optimal neuronal microenvironment, regulating blood-tissue exchange of macromolecules and nutrients. The BBB is characterized by individual endothelial cells that are continuously linked by tight junctions, inhibiting the diffusion of macromolecules and solutes between adjacent endothelial cells. This review will focus on pertinent issues to BBB maintenance, and survey recent dogmas on the transport mechanisms for the essential metal, manganese, across this barrier. Specifically, putative carriers for manganese into and out of the brain will be discussed.

Animals↗

PubMed2005

Antigen presenting cells and HLA-G--a review.

Maternal antigen presenting cells, which are macrophages and dendritic cells, are scattered throughout human decidualized endometrium during all stages of pregnancy. These powerful, multi-functional leukocytes reside in close proximity to uterine glandular epithelium, uterine blood vessels, and HLA-G-producing invasive cytotrophoblast cells. Macrophages and dendritic cells, which express the HLA-G receptors, ILT2 and ILT4, play major roles in driving innate and adaptive immune responses, altering the behavior of local stromal cells, shaping the cytokine microenvironment, and protecting the tissue from infection. Therefore, encounters between decidual antigen presenting cells and HLA-G molecules are likely to influence uterine and placental homeostasis as well as local maternal immune responses to the fetus during pregnancy.

Antigen-Presenting Cells↗

PubMed1998

Immune regulation within the central nervous system.

The brain constitutes an environment that is specifically designed to accommodate, regulate and shape immune responses. On one hand, the central nervous system (CNS) has traditionally been regarded as an immunologically privileged organ, owing to local tissue barrier and immunosuppressive microenvironment. On the other hand, activated microglia and astrocytes express MHC and adhesion/costimulatory molecules, release reactive oxygen intermediates and cytokines, and participate in local immune regulation. Bidirectional interactions between immune and neuroglial components occur in response to infectious and traumatic lesions. Glial cells may facilitate and amplify immune effector mechanisms within the CNS. Cytokines and chemokines within the CNS constitute a specialized CNS-cytokine network, and regulate the development and recovery from autoimmune diseases within the CNS. The interactions between glial cells and lymphoid cells are constituents of a complex immune regulatory system within the CNS. New data on the cross-talk between the CNS and the immune systems are envisaged, and followed by an attempt to create a synthesis of current knowledge.

Animals↗

PubMed1998

The scarring processes in mucosal tissues after immune injury.

OBJECTIVES: An important feature of the healing processes is scar formation which may be necessary for organism survival. If it proceeds to the pathological state, it may impair normal function. The purpose of this review is to focus on some of the factors that may influence this process after immune injury, comparing it in the skin and mucosa. METHODS: A detailed literature search of peer-reviewed journals was conducted. Studies reported in all languages considered relevant and important were used, including humans, animals, and tissue culture. RESULTS: Analysis of the data indicate that the scarring process is mainly dependent on (1) the type of the lesion, (2) the cause and duration of injury, and (3) the tissue involved and its microenvironment. Equally important is the large spectrum and heterogenicity in the biological activity of fibroblasts and their role in scar formation. CONCLUSIONS: The process of scar formation is complex and multistep process and is affected and influenced by local and systemic factors. Although it appears irreversible, there are pharmacological agents available, and under investigation, that may minimize its detrimental effects.

Animals↗