SEARCH · PubMed Health

Results for “tissue microenvironment”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources

PubMed2002

Design and synthesis of a pro-drug of vinblastine targeted at treatment of prostate cancer with enhanced efficacy and reduced systemic toxicity.

Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med.Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T(1/2) = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.

Animals↗

PubMed2004

Effects of pH on the cytotoxicity of sodium trioxodinitrate (Angeli's salt).

Tumor tissues have an acidic microenvironment with a pH from 6.0 to 7.0, whereas the intra- and extracellular milieu of normal cells is 7.4. We have found that the hydrolysis of sodium trioxodinitrate (Angeli's salt; 1) to hydroxyl radical (*OH) was 10 times higher at pH = 6.0 than at pH = 7.4. It is hypothesized that the formation of *OH in solutions of 1 reflects the hydrolysis of the latter compound to nitroxyl (HNO) which dimerizes to cis-hyponitrous acid (HO-N=N-OH; 3) with concomitant azo-type homolytic fission to N(2) and *OH. In weakly acidified solutions, 1 exhibited strong toxicity to cancer cells that was inhibited by scavengers of hydroxyl radical, whereas no toxicity was observed at pH = 7.4. In a subcutaneous xenograft model of pheochromocytoma, 1 markedly inhibited tumor growth at a dose that was nontoxic to nude mice. These data suggest that the H(+)-amplified production of *OH from 1, and maybe other precursors of HNO, could be a selective mechanism for destruction cells with an acidic intra- or extracellular microenvironment.

Animals↗

PubMed2002

Stromal cells from murine embryonic aorta-gonad-mesonephros region, liver and gut mesentery expand human umbilical cord blood-derived CAFC(week6) in extended long-term cultures.

The first definitive long-term repopulating hematopoietic stem cells (HSCs) emerge from and undergo rapid expansion in the embryonic aorta-gonad-mesonephros (AGM) region. To investigate the presumptive unique characteristics of the embryonic hematopoietic microenvironment and its surrounding tissues, we have generated stromal clones from subdissected day 10 and day 11 AGMs, embryonic livers (ELs) and gut mesentery. We here examine the ability of 19 of these clones to sustain extended long-term cultures (LTCs) of human CD34(+) umbilical cord blood (UCB) cells in vitro. The presence of in vitro repopulating cells was assessed by sustained production of progenitor cells (extended LTC-CFC) and cobblestone area-forming cells (CAFC). The embryonic stromal clones differed greatly in their support for human HSCs. Out of eight clones tested in the absence of exogenous cytokines, only one (EL-derived) clone was able to provide maintenance of HSCs. Addition of either Tpo or Flt3-L + Tpo improved the long-term support of about 50% of the tested clones. Cultures on four out of 19 clones, ie the EL-derived clone mentioned, two urogenital-ridge (UG)-derived clones and one gastrointestinal (GI)-derived clone, allowed a continuous expansion of primitive CAFC and CFU-GM with over several hundred-fold more CAFC(week6) produced in the 12th week of culture. This expansion was considerably higher than that found with the FBMD-1 cell line, which is appreciated by many investigators for its support of human HSCs, under comparable conditions. This stromal cell panel derived from the embryonic regions may be a powerful tool in dissecting the factors mediating stromal support for maintenance and expansion of HSCs.

Animals↗

PubMed2006

The therapeutic potential of positive and negative immune cell co-stimulation during inflammation.

Inflammatory cascades are initiated in response to alarm signals that may result from infection, malignant transformation or trauma. Immunity, however, must be controlled; otherwise damage may occur to otherwise healthy tissue within the same microenvironment. Similarly, peripheral tolerance mechanisms must ensure that autoreactive thymic or bone marrow emigrants do not respond upon encounter with the autoantigen. Organized lymphoid structures such as lymph nodes, spleen and Peyer's patches appear to regulate inflammation successfully, displaying controlled expansion and contraction. However, when immune cells flood into effector sites, the organization of T- and B-lymphocytes is lacking. What controls inflammatory cascades in lymph nodes but rarely in effector sites is not clear. We believe the difference lies in the Toll-like receptor ligand load, which is high in effector sites and drives uncontrolled inflammation. Similarly, we believe that initiation of autoimmune inflammation is initiated by the liberation of inflammatory signals due to infection or trauma. In this review, we highlight some of the molecules responsible for maintaining an activated T-cell phenotype, strategies to interrupt these therapeutically and the impact of ligating inhibitory receptors on antigen-presenting cells.

Animals↗

PubMed2003

Expression of CD137 (4-1BB) on human follicular dendritic cells.

Follicular dendritic cells (FDCs) are the antigen (Ag)-trapping accessory cells of the germinal centres (GCs), essential for the development of humoral immune responses and memory. FDCs reside in the microenvironment of secondary lymphoid tissue where Ag-activated B cells expand, and undergo isotype switching and affinity maturation prior to becoming memory B cells. In addition to delivering Ag, FDCs also provide potent nonspecific accessory signals to the B cells, which are important for the GC reaction. In this report, we show that human tonsilar FDCs express the costimulatory molecule CD137. Surface expression of CD137 on FDCs was confirmed by immunofluorescent labelling and fluorescence-activated cell sorter analysis. CD137 was also highly expressed by the human cell line HK, which displays many characteristics of in vivo FDCs. The interaction between B cells and FDCs is essential for the GC reactions, and our finding suggests that CD137 plays a role in FDC-regulated B-cell responses.

Antigens, CD↗

PubMed2000

The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B-cell malignancy.

Like other hepatotropic viruses, hepatitis C virus (HCV) shares the property of inducing hepatocellular damage, possibly through induction of immune mechanisms that lead to hepatocellular necrosis. After infection of hepatocytes, and possibly other cells, humoral and cellular responses occur aimed at prevention of virus dissemination and elimination of infected cells. The early activated mechanisms include production of nonspecific and specific antibodies that represent the first-line of defense against invading foreign pathogens. As a consequence, circulating immune complexes are promptly formed, and antigen uptake and processing by specialized cells are enhanced. A major fraction of circulating immunoglobulins (Igs) are part of the spectrum of the so-called natural antibodies, which include anti-idiotypic antibodies and molecules with rheumatoid factor (RF) activity. They mainly belong to the IgM class, are polyclonal, and have no intrinsic pathogenetic potential. In 20-30% of HCV-infected patients, RFs share characteristics of high affinity molecules, are monoclonal in nature, and result in the production of cold-precipitating immune complexes and mixed cryoglobulinemia. It has been shown that anti-idiotypic antibodies and polyclonal and monoclonal RF molecules have the same cross-reactive idiotype, called WA, suggesting that their production is highly restricted. This strongly indicates that they arise from stimulation with the same antigen, likely HCV. It has also been speculated that B-1 (CD5+) and B-2 (CD5-) B-cell subsets, which use a limited number of VH germline genes, underlie the production of low-affinity polyclonal and high-affinity monoclonal antibodies, respectively. The persistent production of monoclonal RF molecules implies the existence of a further mechanism capable of restricting the reactivity and reflects a distinct selection of a cell population that can be maintained throughout life because they are continuously exposed to antigen pressure. Either polyclonal or monoclonal profiles of B-cell expansion are demonstrable in the liver of most HCV-infected patients. The occurrence of B-cell clonal expansion is strictly related to intrahepatic production of RF molecules, and this suggests that liver is a microenvironment, other than lymphoid tissue, in which a germinal centerlike reaction is induced. The frequent detection of oligoclonal B-cell expansion may, indeed, represent a key pathobiologic feature that sustains nonmalignant B-cell lymphoproliferation. The preferential expansion of one clone would in turn lead to a monoclonal pattern that could favor stochastic oncogenic events. It can be postulated that HCV is the stimulus not only for the apparent benign lymphoproliferative process underlying a wide spectrum of clinical features, but also for the progression to frank lymphoid malignancy in a subgroup of patients. Current data indicate a higher prevalence of overt B-cell non-Hodgkin's lymphoma in HCV-infected patients, especially in some geographic areas.

Autoimmunity↗

PubMed1992

Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

Animals↗

PubMed1998

Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines.

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1-infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4(+) T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4+ T cells derived from HIV-infected individuals who are antiretroviral therapy-naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-alpha, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART.

Anti-HIV Agents↗

PubMed2002

Molecular adaptation of Borrelia burgdorferi in the murine host.

An analysis of expression of 137 lipoprotein genes on the course of murine infection revealed a two-step molecular adaptation by Borrelia burgdorferi, the Lyme disease spirochete. For the first step, regardless whether the initial inocula of B. burgdorferi expressed either all (cultured spirochetes) or less than 40 (host-adapted spirochetes) of the 137 lipoprotein genes, the spirochetes were modulated to transcribe 116 of the genes within 10 d after being introduced to the murine host. This step of adaptation was induced by the microenvironment of the host tissue. During the second step, which was forced by host immune selection pressure and occurred between 17 and 30 d after infection, B. burgdorferi down-regulated most of the lipoprotein genes and expressed less than 40 of the 137 genes. This novel adaptation mechanism could be a critical step for B. burgdorferi to proceed to chronic infection, as the pathogen would be cleared at the early stage of infection if the spirochetes failed to undergo this process.

Adaptation, Physiological↗

PubMed2005

Bone marrow cells differentiate into wound myofibroblasts and accelerate the healing of wounds with exposed bones when combined with an occlusive dressing.

BACKGROUND: The usefulness of bone marrow cells in accelerating wound healing has not been evaluated despite increasing evidence that bone marrow contains mesenchymal stem cells that have multipotentiality to differentiate into various types of cells after they enter the microenvironment of a specific tissue (niche). OBJECTIVES: To determine the effects of bone marrow cells and occlusive dressings in promoting wound healing in rats. METHODS: We investigated by grafting, biopsy and immunohistochemistry whether various types of cells derived from green fluorescent protein (GFP)-transgenic rats would differentiate into wound component cells when administered topically on the wounds of rats. We also investigated whether topical application of bone marrow cells with an occlusive dressing would accelerate the healing of wounds with exposed bones, as measured by planimetry. RESULTS: GFP-labelled bone marrow cells contained multipotent stem cells that sufficiently differentiated into wound myofibroblasts presenting with alpha-smooth muscle actin in granulation tissue. Other types of cells, including myocytes, adipocytes, peripheral blood cells from buffy coat and dermal fibroblasts, did not express myofibroblast characteristics morphologically or immunohistochemically. Application of bone marrow cells and an occlusive dressing accelerated the repair of wounds with exposed bones, compared with an occlusive dressing only or with the topical administration of bone marrow cells plus a semidry to dry dressing. CONCLUSIONS: Our study indicates that bone marrow cells accelerate the healing of wounds at least in part through their differentiation into wound myofibroblasts. Thus, treatment of wounds with bone marrow cells and a supportive occlusive dressing is effective in promoting the formation of healthy granulation tissue and also for the preparation of an ideal wound bed.

Animals↗

PubMed1992

The drug 5-aminosalicylic acid rescues alpha 1-proteinase inhibitor from the neutrophil oxidative inactivation. A possible contribution to its therapeutic action in ulcerative colitis.

The glycoprotein alpha 1-proteinase inhibitor is the specific inhibitor of neutrophil elastase, a major tissue-damaging protease. When incubated with activated neutrophils, alpha 1-proteinase inhibitor lost its pancreatic porcine elastase inhibitory capacity and became incapable of forming a sodium dodecyl sulphate-stable complex with pancreatic porcine elastase. Inhibitors and scavengers of neutrophil-derived reactive oxygen species outlined the crucial role of hypochlorous acid in the alpha 1-proteinase inhibitor inactivation. Moreover, the drug 5-aminosalicylic acid prevented the inactivation of alpha 1-proteinase inhibitor by neutrophils in a dose-dependent manner. Finally, when the capacity of 5-aminosalicylic acid to rescue alpha 1-proteinase inhibitor from the neutrophil-derived attack was plotted as a function of the 5-aminosalicylic acid ability to scavenge neutrophil-derived hypochlorous acid, a positive linear relationship was found. Thus, our results provide a direct evidence that 5-aminosalicylic acid is able to prevent the oxidative inactivation of alpha 1-proteinase inhibitor by neutrophils. Therefore, we suggest that the drug has the potential to limit the elastase-mediated damage of colonic connective tissue by creating a microenvironment of active alpha 1-proteinase inhibitor around the neutrophils.

Aminosalicylic Acids↗

PubMed1988

Hydrocortisone increases the numbers of KL1+ cells, a discrete thymic epithelial cell subset characterized by high molecular weight cytokeratin expression.

The thymic epithelium, a major component of the thymic microenvironment, is a heterogeneous tissue bearing distinct monoclonal antibody-defined subsets. Among these, KL1+ cells represent a mouse medullary subpopulation characterized by high mol wt cytokeratin expression. Given the fact that thymic epithelial cells (TEC) express glucocorticoid receptors and that glucocorticoid hormones are known to modulate the expression of keratins, we decided to study the in vivo effects of hydrocortisone on KL1+ cells in normal and autoimmune mice. Within 24 h after a single injection of this steroid we observed a significant increase in the number of KL1+ cells. Interestingly, this effect was reversible and was no longer detected 7 days after treatment. Parallel studies analyzing the effects of hydrocortisone on the secretion of thymulin, a chemically defined thymic hormone revealed a transient decrease in serum levels of this hormone, but with different kinetics than the effects on KL1+ cells. Ontogenetic studies showed that the responsiveness of TEC to hydrocortisone, in terms of high mol wt cytokeratin expression, appeared late in fetal life and disappeared in aging animals. Importantly, aging, but also young adult, autoimmune mice were not responsive. In vitro experiments using a mouse TEC line confirmed the data observed in vivo demonstrating that the increase in KL1+ cells is a direct effect of hydrocortisone on TEC. The bulk of the data presently reported demonstrates that glucocorticoid hormone can act on TEC modulating the expression of both secretory and cytoskeletal protein families.

Aging↗

PubMed2006

Targeting neuropilin-1 to inhibit VEGF signaling in cancer: Comparison of therapeutic approaches.

Angiogenesis (neovascularization) plays a crucial role in a variety of physiological and pathological conditions including cancer, cardiovascular disease, and wound healing. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Multiple VEGF receptors are expressed on endothelial cells, including signaling receptor tyrosine kinases (VEGFR1 and VEGFR2) and the nonsignaling co-receptor Neuropilin-1. Neuropilin-1 binds only the isoform of VEGF responsible for pathological angiogenesis (VEGF165), and is thus a potential target for inhibiting VEGF signaling. Using the first molecularly detailed computational model of VEGF and its receptors, we have shown previously that the VEGFR-Neuropilin interactions explain the observed differential effects of VEGF isoforms on VEGF signaling in vitro, and demonstrated potent VEGF inhibition by an antibody to Neuropilin-1 that does not block ligand binding but blocks subsequent receptor coupling. In the present study, we extend that computational model to simulation of in vivo VEGF transport and binding, and predict the in vivo efficacy of several Neuropilin-targeted therapies in inhibiting VEGF signaling: (a) blocking Neuropilin-1 expression; (b) blocking VEGF binding to Neuropilin-1; (c) blocking Neuropilin-VEGFR coupling. The model predicts that blockade of Neuropilin-VEGFR coupling is significantly more effective than other approaches in decreasing VEGF-VEGFR2 signaling. In addition, tumor types with different receptor expression levels respond differently to each of these treatments. In designing human therapeutics, the mechanism of attacking the target plays a significant role in the outcome: of the strategies tested here, drugs with similar properties to the Neuropilin-1 antibody are predicted to be most effective. The tumor type and the microenvironment of the target tissue are also significant in determining therapeutic efficacy of each of the treatments studied.

Biological Transport↗

PubMed2026

A Practical Workflow for Spatial Transcriptomics Data Analysis: From Data Acquisition to Advanced Analyses.

Spatial transcriptomics (ST) profiles genome-wide gene expression while preserving the two-dimensional spatial context of mRNA molecules within tissue sections, enabling studies of tissue architecture and microenvironment-associated biology. However, ST analysis remains challenging because data import, quality control, integration, deconvolution, spatial statistics, and visualization often require multiple software environments and reproducible parameter choices. This protocol presents a practical computational workflow for public ST datasets in R, beginning with data acquisition and software setup and proceeding through Seurat-based data loading, quality control, normalization, multi-sample integration, clustering, and spatially variable gene analysis. The workflow then applies complementary deconvolution strategies, including reference-guided SPOTlight analysis and unsupervised STdeconvolve topic modeling, followed by Giotto-based spatial cell-cell communication analysis and interactive region-of-interest (ROI) selection using a custom Python Dash application. By emphasizing script-based execution, explicit parameter rationales, expected outputs, and troubleshooting checkpoints, the protocol provides an adaptable framework for standard array-based ST datasets and related platforms after dataset- and platform-specific parameter evaluation.

Spatial Transcriptomics↗

PubMedDate not supplied

Role of RGS proteins in regulating the migration of B lymphocytes.

The migration of B lymphocytes into distinct microenvironments in secondary lymphoid tissues and maintenance of cells in these micro-domains is strictly structured and likely supports the proper regulation of immune responses to both foreign and self-antigens. Chemokines' and other chemoattactants' signals serve as signposts to direct cell migration. They signal cells through heptahelical receptors, which couple to heterotrimeric G proteins (G protein-coupled receptors or GPCRs). The regulation of the signals transduced through these receptors ultimately determines the positioning of cells in lymphoid tissues. A variety of mechanisms regulate GPCR signaling including a family of approximately 25 proteins termed regulators of G protein signaling (RGS). These proteins act as GTPase activating proteins for G alpha subunits and can also function as effector antagonists of specific G alpha subunits, thereby attenuating signaling through GPCRs such as chemokine receptors. RGS proteins possess some degree of receptor and G alpha subunit specificity. Thus, the particular spectrum of RGS proteins and their expression levels within a cell will determine the duration and magnitude of G protein signaling initiated by chemokines. In this review we illustrate the role RGS proteins have in regulating B cell signaling responses to chemoattractant stimuli during homeostasis as well as during an immune response.

Animals↗

PubMed2004

[The blood system and the organism adaptation to extreme factor].

The formation of blood system adoptive reaction in many cases is defined by the type of action and the condition of hemopoietic inductive microenvironment: hemodynamics of hemopoietic tissue, functional conditions of bone marrow macrophages, mast cells and glycosaminoglycans content. The shift in hemodlobin fraction occurs in extreme conditions requiring an increased gas transport by the blood. In case of tissue lesion, lymphocytes stimulate their regeneration. Morphogenetic function of lymphoid cells may be alerted by immunomodulators. Blood cells participate in angiogenesis, and this property may be used for vessel grafts production.

Adaptation, Physiological↗

PubMed1987

Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro.

Interleukin 1 (IL-1) plays an important role in host defense mechanisms by increasing body temperature, inducing the synthesis of a variety of lymphokines and hepatic acute phase proteins and acting as a chemoattractant for lymphocytes. However, in some microenvironments such as injured tissue or joint spaces, elevated IL-1 levels may contribute to pathologic processes, for example, proliferation and fibrosis of tissue involved in pannus formation as well as degradation of matrix and abnormal tissue architecture. To investigate potential mechanisms that may lead to excessive production of IL-1, we have examined the ability of IL-1 to participate in an amplification event by inducing its own gene expression leading to synthesis of biologically active IL-1. When injected into rabbits, recombinant human IL-1-alpha induced biphasic fevers, and during the second temperature elevation 3 hr later, a circulating pyrogenic material was detected by passive transfer of plasma to other rabbits. Induction of the biphasic fever was not caused by endotoxin contamination of the recombinant IL-1. The 3-hr circulating pyrogen was heat-labile and was not residual injected IL-1-alpha. Chromatographic separation of this plasma and biologic assay suggested that it was new IL-1 of rabbit origin. We next incubated human blood mononuclear cells with recombinant IL-1-alpha and measured the intracellular and extracellular levels of IL-1 by bioassay using the D10.G4.1 murine T cell line. In order to control for the carryover of recombinant IL-1-alpha used to stimulate the mononuclear cells (MNC), we used neutralizing antibodies that were specific for IL-1-alpha or IL-1-beta. The results of these neutralizations showed that recombinant human IL-1-alpha induces the synthesis of IL-1-beta in human MNC in vitro. These results were verified with a radioimmunoassay specific for IL-1-beta. At concentrations of 100 ng/ml, IL-1-alpha induced prostaglandin E2 production in the MNC culture, and this was associated with decreased production of immunoreactive IL-1-beta. Adding indomethacin to the cultures prevented the decreased production of IL-1-beta induced by high concentrations of IL-1-alpha. Using nonadherent MNC, we observed an increase in IL-1-beta as well as IL-1-alpha mRNA after 4 hr of exposure to recombinant IL-1-alpha. These results demonstrate that IL-1-alpha induces biologically active and immunoreactive IL-1-beta from MNC in vitro and that the same concentrations of IL-1-alpha induce gene expression for both forms of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

The human thymic microenvironment: cortical thymic epithelium is an antigenically distinct region of the thymic microenvironment.

The thymic microenvironment is a complex tissue essential for normal T cell maturation. Prothymocytes in the subcapsular cortical (SCC) region of the thymus undergo cell division and migrate to the inner cortex. The majority of cortical thymocytes cease dividing and die, but a minority are exported to the periphery. We have previously shown thymic hormones in SCC and medullary thymic epithelium and have identified a monoclonal antibody (TE-4) that defines human endocrine thymic epithelium. However, no marker that selectively defines cortical thymic epithelium has been available. In this study, we have produced two monoclonal antibodies, TE-3A and TE-3B, raised against human thymic stroma that bind to an intracellular antigen in cortical but not medullary thymic epithelium. In double immunofluorescence assays in which we used anti-keratin, anti-thymosin alpha 1, and anti-endocrine thymic epithelium antibodies (TE-4, A2B5), TE-3+ SCC epithelium was TE-4+ and contained keratin and thymosin. alpha 1. In contrast, TE-3+ inner cortical epithelium was TE-4/A2B5 nonreactive and did not contain thymosin alpha 1. An ontogeny study of seven fetal and five neonatal thymuses demonstrated that expression of the TE-3 antigen was acquired at 10 wk fetal gestation. Using TE-3 antibody, we observed sequential stages of separation of cortical and medullary epithelium from 12 to 20 wk fetal gestation. In dysplastic (severe combined immunodeficiency disease) thymuses, strands of TE-3+ nonendocrine cells encircled nests of TE-4+ endocrine epithelium. Thus, human cortical thymic epithelium is antigenically distinct from endocrine medullary epithelium. Antibodies against the TE-3 antigen define an intracellular molecule that may reflect a specialized function of cortical thymic epithelium.

Adolescent↗