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Results for “tissue microenvironment”

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PubMed2004

The immunoregulatory effects of homocysteine and its intermediates on T-lymphocyte function.

Elevated levels of homocysteine (Hcy) have been identified as independent risk identifiers for cardiovascular disease, cerebrovascular disease as well as for all-cause mortality. Despite the potential importance of these observations, a definitive pathological role for Hcy or its various metabolites in any of these conditions has not been established. Particularly deficient is a description of the effects of elevated levels of homocysteine on immune function. Folic acid and vitamin B12 deficiency have been independently associated with decreased immune function, the apoptosis of bone marrow hematopoietic progenitor cells and the appearance of leukocytes with hypomethylated DNA in the peripheral circulation. A specific role for Hcy or its metabolites in these processes has not been described. We have examined the effects of Hcy and its various derivatives on T cell activation, differentiation and cell viability. Our results have demonstrated that Hcy is a potent concentration-dependent T cell activator promoting cellular activation and differentiation as well as potentiating activation-induced cell death (AICD) and cellular apoptosis. Overall, Hcy appears to exert diverse effects on immune function in the circulation and within the tissue microenvironment possibly contributing to age-related immune dysfunction and disease pathology.

Aged↗

PubMed2005

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation.

Nuclear factor of activated T (NFAT) cells is a family of transcription factors important for the regulation of cytokine expression by CD4+ T cells. Whilst a number of studies have examined NFAT activity of in vitro generated CD4+ T helper (Th)1 and Th2 cells, regulation of NFAT during in vivo immune responses has yet to be elucidated. We show that NFAT activity in CD4+ T cells peaked at early time-points in the draining mediastinal lymph node of mice infected with influenza A (Flu) or Nippostrongylus brasiliensis (Nb). In contrast, low NFAT transcriptional activity was detected in CD4+ T cells isolated from the lung of either Flu or Nb infected mice, despite a greater proportion of cytokine-producing cells being present at this site. These findings indicate that the activation status and tissue microenvironment of effector CD4+ T cells can determine their requirement for NFAT-mediated transcription.

Animals↗

PubMed2005

Microenvironmental control of premalignant disease: the role of intercellular adhesion in the progression of squamous cell carcinoma.

Interactions between potentially neoplastic cells and their normal neighbors act as an important microenvironmental control during the premalignant, intraepithelial (IE) stage of squamous cell cancer development. Using human three-dimensional (3D) tissue models, it has been shown that such interactions induce a state of IE dormancy in which cancer progression is suppressed. This dormant state can be overcome by altering tissue dynamics in response to the tumor promoter TPA, UV irradiation, decreasing adhesive interactions between tumor cells and adjacent epithelia or enabling tumor cells to interact with basement membrane proteins. This chapter will provide an overview of investigations that have characterized how the tissue microenvironment can regulate the incipient development of squamous cell carcinoma.

Animals↗

PubMed2006

Porcine epidermal stem cells as a biomedical model for wound healing and normal/malignant epithelial cell propagation.

This article summarizes research using cells derived from epidermis of the miniature pigs for use as a cell therapy for skin repair and as a model for squamous carcinoma of the head and neck. Stem cells are an important "tool" for biomedical research. Adult stem cells are defined functionally, as cells that have the capacity to self-renew as well as the ability to generate differentiated cells. They are present in defined tissue microenvironments called niches. Asymmetric mitosis allows them to produce one daughter cell with the properties of stem cells (self-renewal) and a second cell with characteristics of progenitor cells, or transit amplifying cells, which proliferate quickly but with a limited number of mitotic divisions. Porcine epidermal stem cells, located in the bulge region of the outer root sheath of hair follicles, migrate in vitro from hair sheaths and because they are resistant to anoikis (detachment induced apoptosis), survive in non-adhesive conditions to form spheroids. These cells express keratins, galectin-1 and their nuclei are rich in DeltaNp63alpha. Interestingly, the multiple phenotype analysis of the human tumor cells in squamous carcinoma of head and neck revealed similarities with epidermal stem cells. These cancer stem cells are usually located on the periphery of the tumor where the invasive front of the tumor responsible for its aggressive behavior is located. In contrast, extensive expression of markers of terminal differentiation such as expression of glycoligands reactive for the endogenous lectin, galectin-3, indicates better tumor prognosis.

Animals↗

PubMed2006

Plant stem cells carve their own niche.

Stem cells are the precursors of differentiated cells and are, thus, indispensable for growth and development in plants and animals. Stem cells from both types of organisms share the fundamental features of a capacity for self-renewal and an ability to generate differentiated cells. The maintenance of stem cells in both systems is dependent upon reciprocal signalling between stem cells and the specialized tissue microenvironment known as the niche, which provides intercellular signals for stem cell regulation. One significantly underexplored facet of plant stem cells is the nature of their intrinsic transcriptional programme. A potentially rich avenue for addressing this deficiency is to combine laser-assisted microdissection and genome-wide transcriptional profiling to unravel the molecular road map controlling plant stem cells and their niches.

Animals↗

PubMed2004

Life-long systemic protection in mice vaccinated with L. major and adenovirus IL-12 vector requires active infection, macrophages and intact lymph nodes.

Immunization with soluble leishmanial antigen (SLA) in IFA plus Ad5IL-12 vector induced protection confined to the immunized footpad in BALB/c mice. However, animals that controlled a primary infection with a Leishmania major challenge in the same immunized footpad, became resistant to subsequent contralateral rechallenges due to expansion of IFN-gamma secreting cells. This systemic immunity could be disrupted either by macrophage depletion during immunization or by lymphadenectomy after challenge. We show that this procedure does not interfere with tissue-compartmentalized protection, since lymphadenectomized and splenectomized animals were resistant to rechallenges performed in the immunized footpads. Our results indicate that SLA-Ad5IL-12 vector priming requires macrophages to generate systemic protection. Furthermore, a previously undescribed lymphoid organ-independent, protective immune response is contained within the tissue microenvironment of the immunized/challenged footpad. These results have important implications for vaccine design against leishmanial and mycobacterial infections and diseases caused by intracellular pathogens.

Adenoviridae↗

PubMedDate not supplied

Avian macrophage: effector functions in health and disease.

Monocytes-macrophages, cells belonging to the mononuclear phagocytic system, are considered as the first line of immunological defense. Being mobile scavenger cells, macrophages participate in innate immunity by serving as phagocytic cells. These cells arise in the bone marrow and subsequently enter the blood circulation as blood monocytes. Upon migration to various tissues, monocytes mature and differentiate into tissue macrophages. Macrophages then initiate the 'acquired' immune response in their capacity as antigen processing and presenting cells. While responding to their tissue microenvironment or exogenous antigenic challenge, macrophages may secrete several immunoregulatory cytokines or metabolites. Being the first line of immunological defense, macrophages therefore represent an important step during interaction with infectious agents. The outcome of the macrophage-pathogen interaction depends upon several factors including the stage of macrophage activation, the nature of the infectious agent, the level of genetic control on macrophage function as well as environmental and nutritional factors that may modulate macrophage activation and functions. Research in avian macrophages has lagged behind that in mammals. This has been largely due to the lack of harvestable resident macrophages from the chicken peritoneal cavity. However, the development of elicitation protocols to harvest inflammatory abdominal macrophages and the availability of transformed chicken macrophage cell lines, has enabled researchers to address several questions related to chicken macrophage biology and function in health and disease. In this manuscript the basic profiles of several macrophage effector functions are described. In addition, the interaction of macrophages with various pathogens as well as the effect of genetic and environmental factors on macrophage functional modulation is described.

Animals↗

PubMed2003

Why are dendritic cells important in allergic diseases of the respiratory tract?

Increasing evidence points to the role of antigen-presenting dendritic cells (DC) in regulating adaptive immune responses. DC are especially sensitive to signals derived from microbes, allergens, and the airway tissue microenvironment, can polarize naïve T-cells into either Th1 or Th2 effector cells, and are increasingly recognized as having a central role in the establishment of T-cell memory and tolerance to inhaled antigens. DC form a closely meshed network within the respiratory mucosa and are rapidly recruited from the circulation in response to a variety of proinflammatory stimuli. Studies using animal models have highlighted the role of DC in both initiation and maintenance of allergic airway inflammation. Increased numbers of airway mucosal DC are found in both allergic rhinitis and asthma, and an increasing number of investigators have highlighted important functional differences between DC from atopic and normal individuals. This article reviews recent information on the involvement of DC in the pathogenesis of allergic airway disease and the means by which DC could be exploited as targets for therapy in asthma and allergic rhinitis.

Allergens↗

PubMed1994

BCG-induced granuloma formation in murine tissues.

BCG infection of mice provides a convenient model to study natural and cellular immunity to mycobacteria and the mechanisms of granuloma formation and repair. We have used a range of macrophage (M phi) membrane molecules and secretory products to investigate resident M phi-pathogen interactions and T lymphocyte-dependent recruitment and activation of M phi in different tissues of immature, normal adult and gamma interferon deficient animals. In situ hybridization (ISH), RT-PCR and immunocytochemical analysis of M phi gene and product expression have been correlated with in vitro study of endocytic and secretory activity in which biogel polyacrylamide bead-elicited peritoneal M phi are exposed to Th1 and Th2 cytokines, LPS, BCG and other stimuli. The role of resident and newly recruited M phi responding to BCG in liver, spleen, lung and brain has been defined by means of antigen markers expressed by M phi (F4/80, 7/4, CR3, macrosialin, sialoadhesin and scavenger receptor) and/or T and B lymphoid cells (MHC Class II, CD4, CD8, B220). Heterogeneity in M phi secretory activity was revealed by ISH analysis of lysozyme, TNF-alpha, IL-1 IL-6 and MCP-1, by in vitro assay of NO and superoxide anion production, and by RT-PCR studies of Th1 (interferon gamma) and Th2 (IL-4, IL-13, IL-10) lymphokine mRNA in tissues. Our studies confirm the importance of interferon gamma as a critical mediator of host resistance to mycobacterial infection and raise intriguing questions in regard to T cell and M phi functional heterogeneity in distinct tissue microenvironments.

Animals↗

PubMed2000

High-performance liquid chromatographic analysis of muscular interstitial arginine and norepinephrine kinetics. A microdialysis study in rats.

Complex interactions between the L-arginine/nitric oxide synthase (NOS) pathway and the sympathetic nervous system have been reported. Methods capable of measuring L-arginine and norepinephrine (NE) have mainly been reported for plasma. We report the use of the microdialysis technique combined with high-performance liquid chromatography (HPLC) for measurement of both L-arginine and NE within the same tissue microdialysis sample. The microdialysis probe consisted of linear flexible probes (membrane length: 10 mm, outside diameter: 290 microm, molecular weight cut-off 50 kDa). The method used for L-arginine measurement was HPLC with fluorescence detection, giving a within-run and a between-day coefficient of variation of 2.9 and 12.8%, respectively. The detection limit was 0.5 pM/20 microl injected for L-/D-arginine. The method used for NE measurement was HPLC with electrochemical detection. The coefficients of variation were 4% for within-assay precision and 7.5% for between-assay precision. The detection limit for NE was 1 fmol/20 microl injected. The microdialysis technique coupled with HPLC system was validated in vivo to measure muscular interstitial concentrations of both arginine and NE under baseline conditions and after intravenous infusion of 500 mg/kg of L-arginine or D-arginine. In conclusion, the microdialysis technique coupled to HPLC allows the simultaneous measurements of both L-arginine and NE within the same tissue microenvironment and will enable the study of the complex interactions between the L-arginine/NO pathway and sympathetic nervous system within the interstitial space of different organs.

Animals↗

PubMed2001

Zymographic analysis of circulating and tissue forms of colon carcinoma gelatinase A (MMP-2) and B (MMP-9) separated by mono- and two-dimensional electrophoresis.

Gelatinase A (MMP-2) and gelatinase B (MMP-9) play a key role in the proteolytic cascade leading to ECM degradation during invasion and metastasis. The enzyme activity is regulated both at the intra- and extra-cellular level. Extracellular regulation is achieved mainly through the balance between proenzyme activation and inhibition, which appears to be altered in cancer patients. One of the mechanisms of MMP inhibition is the binding of the enzymes to appropriate tissue inhibitors (TIMP). In the recent literature, it has been suggested that MMP-2 and/or MMP-9 are indeed over-produced in many carcinomas, while the identity of the various enzymatic forms (latent, activated and enzyme/inhibitor complexes) remains to be elucidated. In this study we have analyzed the circulating forms of MMP-9 and MMP-2 in serum samples of patients with colon carcinoma, as well as the enzymatic activities present in tissue extracts from surgical fragments (primary tumor and its paired healthy tissue). Proteins were separated by means of mono-dimensional or bidimensional electrophoresis, and the enzymes detected by gelatin zymography and immunological assays. The results of densitometric analyses demonstrate that proMMP-9, but not proMMP-2, is significantly higher in the oncologic sera vs. the normal sera. In addition, several oligomeric circulating and tissue forms of MMP-9 are preferentially found in the oncologic samples, both in mono- and second-dimension zymograms. The activated forms of MMP-2 and MMP-9 are uniquely present in the primary tumor extracts, thus confirming the involvement of the tissue microenvironment in gelatinase activation and function.

Adult↗

PubMedDate not supplied

Effects of matrix components on aromatase activity in breast stromal cells in culture.

Local estradiol production within breast tissue is maintained by the aromatase cytochrome P450arom complex, which has been localized primarily to the stromal component of tumors but also has been detected in the breast epithelial cells. Paracrine interactions between stromal and epithelial components of the breast are critical to the sustained growth and progression of breast tumors. Maintenance of the differentiated state, including hormone and growth factor responsiveness, requires extracellular matrix proteins as substrata for cells. This research has focused on developing a cell culture system that more closely mimics in vivo interactions in order to dissect actual paracrine signaling between these two cell types. Human fibroblasts were isolated from breast tissue and were maintained in a cell culture system grown on plastic support or on a collagen I support matrix. The collagen I matrix model supports cell maintenance and subsequent differentiation on collagen rather than maximal proliferation, therefore allowing for a more accurate environment for the study of hormonal control and cellular communication. Initial experiments compared aromatase activity of patient fibroblasts grown on plastic versus collagen I using the tritiated water release method. Constitutive aromatase activity was found to be lower when cells were grown on a collagen gel for 4-7 days (7.7 fold lower) using DMEM/F12 containing 10% dextran coated charcoal stripped serum. However, fibroblasts grown on collagen I appeared to be significantly more responsive to stimulation by 100 nM dexamethasone (plastic: 6.0 fold induction, collagen: 33.2 fold induction) when pretreated for 12 h prior to measurement of aromatase activity. In an effort to examine paracrine interactions between the stromal and epithelial cells in breast tissue, experiments using conditioned media from fibroblast cultures were performed. Testosterone administration to fibroblasts results in the production of estradiol into the media in sufficient concentrations to elicit an increase in pS2 expression when the conditioned media is administered to MCF-7 cells. The addition of a potent aromatase inhibitor resulted in a complete suppression of fibroblast-derived estrogens and showed only a modest increase in pS2 expression. Culturing breast fibroblasts and epithelial cells on extracellular matrix allows for a more meaningful examination of the paracrine interactions between these cell types within the context of an appropriate extracellular environment. This study highlights the need for evaluation of gene expression in cell culture systems that accurately reflect the tissue microenvironment.

Adenocarcinoma↗

PubMed2001

Role of IL-10 in allergen-specific immunotherapy and normal response to allergens.

Induction of specific unresponsiveness (tolerance/anergy) in peripheral T cells by interleukin-10 (IL-10) and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy of allergy and in natural exposure to allergens in healthy individuals. IL-10 elicits anergy in T cells by selective inhibition of the CD28 costimulatory pathway and controls suppression and development of antigen-specific immunity.

Allergens↗

PubMed2004

Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment.

Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.

Actin Cytoskeleton↗

PubMed1998

Growth and dissemination of a newly-established murine B-cell lymphoma cell line is inhibited by multimeric YIGSR peptide.

B-cell lymphoma frequently shows simultaneous dissemination to multiple organs. It also occasionally involves bone and causes osteolytic lesions. To study the mechanisms responsible for this capacity of lymphoma cells to grow in different tissue microenvironments and search for effective therapeutic interventions for this hematological malignancy, we established a new murine B-cell lymphoma cell line named MH-95. The tumor disseminated to multiple organs including the lung, liver, kidney, spleen and lymph nodes within 2 weeks after subcutaneous inoculation in nude mice. In addition, the tumor also grew in bone and caused osteoclastic osteolytic lesions. Thus, this tumor model mimics the behavior in many ways of B-cell lymphoma in humans. We studied the role of laminin, a major component of the basement membrane, in this model, since although it has been implicated in solid tumor metastasis, little is known about the involvement of laminin in the growth of B-cell lymphoma in bone and other organs. Immunohistochemical examination showed strong laminin expression in the stroma of the primary subcutaneous tumor and tumors in the bone and other organs. Systemic administration of the antagonistic laminin peptide YIGSR decreased primary tumor growth and tumor cell deposit in the bone, liver and kidney. In addition, the peptide also decreased apparent neovascularization in the tumor, suggesting that the peptide suppressed angiogenesis presumably due to inhibition of laminin binding to its receptors. These results demonstrate that the MH-95 B-cell lymphoma cells express laminin and suggest that laminin plays a critical role in the growth and simultaneous dissemination of tumor cells to multiple organs, similar to what has been described in solid tumors. The results also suggest that suppression of angiogenesis through interfering with laminin actions may be a useful adjuvant therapy for B-cell lymphoma.

Amino Acids, Diamino↗

PubMed2003

Neoplastic development in plasma cells.

An increasing number of model systems of plasma cell tumor (PCT) formation have been and are being developed. Discussed here are six models in mice and multiple myeloma (MM) in humans. Each model illustrates a unique set of biological factors. There are two general types of model systems: those that depend upon naturally arising mutagenic changes (pristane-induced PCTs, 5TMM, and MM) and those that are associated with oncogenes (Emu-v-abl), growth factors [interleukin-6 (IL-6)], and anti-apoptotic factors (Bcl-xL/Bcl-2). PCTs develop in several special tissue microenvironments that provide essential cytokines (IL-6) and cell-cell interactions. In mice, the activation and deregulation of c-myc by chromosomal translocations is a major feature in many of the models. This mechanism is much less a factor in MM and the 5T model in mice. Genetically determined susceptibility is involved in many of the mouse models, but only a few genes have been implicated thus far.

Animals↗

PubMed2006

Toll-dependent selection of microbial antigens for presentation by dendritic cells.

Dendritic cells constitutively sample the tissue microenvironment and phagocytose both microbial and host apoptotic cells. This leads to the induction of immunity against invading pathogens or tolerance to peripheral self antigens, respectively. The outcome of antigen presentation by dendritic cells depends on their activation status, such that Toll-like receptor (TLR)-induced dendritic cell activation makes them immunogenic, whereas steady-state presentation of self antigens leads to tolerance. TLR-inducible expression of co-stimulatory signals is one of the mechanisms of self/non-self discrimination. However, it is unclear whether or how the inducible expression of co-stimulatory signals would distinguish between self antigens and microbial antigens when both are encountered by dendritic cells during infection. Here we describe a new mechanism of antigen selection in dendritic cells for presentation by major histocompatibility complex class II molecules (MHC II) that is based on the origin of the antigen. We show that the efficiency of presenting antigens from phagocytosed cargo is dependent on the presence of TLR ligands within the cargo. Furthermore, we show that the generation of peptide-MHC class II complexes is controlled by TLRs in a strictly phagosome-autonomous manner.

Animals↗

PubMed2004

Direct proteomic mapping of the lung microvascular endothelial cell surface in vivo and in cell culture.

Endothelial cells can function differently in vitro and in vivo; however, the degree of microenvironmental modulation in vivo remains unknown at the molecular level largely because of analytical limitations. We use multidimensional protein identification technology (MudPIT) to identify 450 proteins (with three or more spectra) in luminal endothelial cell plasma membranes isolated from rat lungs and from cultured rat lung microvascular endothelial cells. Forty-one percent of proteins expressed in vivo are not detected in vitro. Statistical analysis measuring reproducibility reveals that seven to ten MudPIT measurements are necessary to achieve > or =95% confidence of analytical completeness with current ion trap equipment. Large-scale mapping of the proteome of vascular endothelial cell surface in vivo, as demonstrated here, is advisable because distinct protein expression is apparently regulated by the tissue microenvironment that cannot yet be duplicated in standard cell culture.

Animals↗