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PubMed1979

The basophil. Its morphology, biochemistry, motility, release reactions, recovery, and role in the inflammatory responses of IgE-mediated and cell-mediated origin.

The current state of our knowledge of basophils is reviewed. Much has recently been learned about these cells-their morphology, biochemical contents, interactions with homocytotropic antibodies, release of mediators in anaphylaxis, capacity for ingesting and releasing exogenous tracers, motility, participation in and progressive degranulation in cell-mediated hypersensitivity reactions, and their recovery from degranulation. It seems unlikely that basophils exist to destroy the organism by anaphylactic shock. Nonetheless, basophil function is probably closely related to the potent chemicals stored in their cytoplasmic granules. Perhaps small amounts of these chemicals are required for homeostasis and these cells function by releasing such substances as they are needed. This hypothesis requires that basophils be capable of releasing their contents slowly and piecemeal, which apparently occurs. This hypothesis also requires that physiological, rather than pharmacological, roles be found for histamine.

Animals↗
PubMed1980

Studies on stimulation of cell-mediated cytotoxicity by skin test antigens. I. Candida antigen stimulation of cell-mediated cytotoxicity in vitro correlated with the skin test response to candida antigen in vivo.

The magnitude of the skin test response in a group of normal volunteers to intradermal Candida antigen correlated closely with the level of cytolytic activity stimulated by Candida antigen in vitro in the peripheral blood lymphocytes from those same individuals. The cytolytic activity stimulated by Candida antigen was cell mediated, and cold target inhibition studies demonstrated that Candida antigen-stimulated effector cells were capable of cross-species (i.e., nonspecific) killing. Analysis of the Candida antigen-induced effector cell population for various cell markers did not enable absolute identification of the cell responsible for the killing. The findings in this study indicate that the stimulation of cell-mediated cytolysis by Candida antigen may be related to the delayed-type hypersensitivity response produced by the same antigen.

Animals↗
PubMed1982

Phagocytosis by rat peritoneal mast cells: independence of IgG Fc-mediated and C3-mediated signals.

Phagocytosis of sheep erythrocytes (E) bearing rabbit immunoglobulin and rat C3 by rat peritoneal mast cells was quantitated by using 51Cr-labeled E and was confirmed by electron microscopy. The relative importance of IgG Fc receptor interaction in C3-mediated phagocytosis was assessed. Removal of any traces of IgG antibody by absorption of IgM antibody with protein A-Sepharose and absorption of the other reagents with sheep E had no effect on the phagocytosis of C3b- and C3bi-coated cells. IgG antibody enhanced the phagocytosis of intermediates prepared with IgM, purified components and rat C3 (EaIgMClgp4hu oxy2hu3brat) with a graded dose response, but was only additive and not synergistic with C3. The independence of the C3- and Fc-mediated signals was confirmed by using chemically produced polymers of rabbit IgG to inhibit phagocytosis. These polymers, especially tetramers and higher aggregates, completely blocked ingestion of EAIgG, but not that of EAIgMC1423b or -3bi. When IgG was substituted for IgM in the C3b intermediate, the IgG polymers inhibited about 50% of the phagocytosis. Cumulatively, the data demonstrated that in the case of rat mast cells, the stimuli to phagocytosis induced by C3 and IgG are independent; either is sufficient by itself.

Animals↗
PubMed1980

Membrane structure-function relationships in cell-mediated cytolysis. I. Effect of exogenously incorporated fatty acids on effector cell function in cell-mediated cytolysis.

The fatty acid composition of the membrane phospholipids of CTL memory cells restimulated with Con A can be altered significantly when selected exogenous fatty acids are present during the restimulation culture period. Such alterations also lead to significant changes in the subsequent cytolytic capacity of the regenerated CTL. Unsaturated fatty acids increase cytotoxicity, whereas saturated fatty acids lead to decreased cytotoxic function. The kinetics of the fatty acid effect on CTL function is the same as the kinetics of fatty acid incorporation into membrane phospholipids, suggesting that alteration of cytotoxicity results from altering membrane phospholipid fatty acid composition. The initial studies reported here suggest that this effect is mediated at the level of individual CTL, rather than through an alteration of CTL frequency in effector cell populations. Moreover, it seems unlikely that the fatty acids mediate their effect by altering membrane fluidity.

Amino Acids↗
PubMed1981

Direct in vitro evidence for different susceptibilities to 4-hydroperoxycyclophosphamide of antigen-primed T cells regulating humoral and cell-mediated immune responses to sheep erythrocytes: a possible explanation for the inverse action of cyclophosphamide on humoral and cell-mediated immune responses.

Suppressor T cells of humoral immune responses, effector T cells mediating DTH, suppressor T cells of DTH, and helper T cells of humoral immune responses, all with specificity to SRBC, were produced in mice. The biologic activity was tested in adoptive transfer experiments. In vitro treatment with different doses of 4-hydroperoxycyclophosphamide (4-HPCy) yielded the result that the various activities tested were not uniformly sensitive to the action of this drug: Suppressor T cells of humoral immune responses and effector T cells mediating DTH were resistant to doses of 4-HPCy that eliminated the activities of suppressor T cells of DTH and helper cells of the humoral immune response. These findings help to explain the various effects cyclophosphamide has on the in vivo immune response and may help to form a basis for the rational manipulation of the immune response by drugs that selectively affect different subgroups of immune cells.

Animals↗
PubMed1983

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity and spontaneous cytotoxicity in normals and cancer patients as assayed by human erythrocyte lysis.

The monocyte-macrophage system has long been recognized as a necessary accessory to the immune response. Recently, however, monocyte-macrophages have been shown to be important effectors of cell-mediated cellular cytotoxicity (both antibody dependent and antibody independent). In this study, monocyte-mediated cellular cytotoxicity of both types was assessed on 51Cr-labeled human erythrocytes (type B+) using autologous and standardized AB serum, and monocytes from 57 normal controls, 16 women with benign breast disease, and 175 patients with cancers of the breast (44 patients), colorectum (46 patients), head and neck (33 patients), lung (13 patients), and melanoma (39 patients). Although results were variable, many of the patients had depressed antibody-dependent cellular cytotoxicity suggesting decreased ability of their monocyte-macrophage to lyse the sensitized erythrocytes. Enhanced antibody-dependent cellular cytotoxicity was observed in patients with localized colorectal cancer, but this effect was reversed in patients with advanced disease. Serum factors did not significantly affect responses in most cases. The clinical relevance of this assay remains to be determined.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1977

III. Mediators of allergic reactions. Endogenous and exogenous stimulating or suppressor substances. Mediators of experimental hypersensitivity pneumonitis.

Using a physiologic model of hypersensitivity pneumonitis where depressions of arterial oxygen tension in unimmunized rabbits are monitored following aerosol challenge with Aspergillus terreus spores, attempts were made to assess the nature of the cellular and pharmacologic mediators of the impairment. Unlike normal animals no PaO2 depressions were obtained following aerosol challenge in either rabbits deficient in C6 or in rabbits made thrombocytopenic with antiplatelet serum. Such aerosols were also shown to produce platelet count depressions of up to 45% in normal rabbits. Finally, in vitro evidence of histamine release was obtained following incubation of Aspergillus extract, platelets and autologous serum from unimmunized rabbits. It was concluded that Aspergillus-induced pulmonary disease may be initiated by platelet release of mediators such as histamine stimulated by nonspecific complement activation.

Aerosols↗
PubMed1980

Scanning and transmission electron microscopic studies of complement-mediated lysis and antibody-dependent cell-mediated cytolysis of herpes simplex virus-infected human fibroblasts.

The morphologic aspects of complement-mediated and antibody-dependent cell-mediated cytolysis (ADCC) of human fibroblasts (HuFs) infected by herpes simplex virus (HSV) is described. Human antiviral antibody (antiHSV) was shown by transmission and scanning electron microscopy (TEM and SEM) to cause the deposition of an amorphous material over the surface of infected cells and virus particles. Associated with antiHSV treatment, the HuFs underwent endocytosis, with the appearance of pinocytotic vesicles immediately beneath the plasma membrane. The addition of complement resulted in lysis of the infected HuFs and massive dilatation of the perinuclear cisternae, but the virus particles associated with the cell surface did not appear lysed. Instead, an additional deposit was noted on the enveloped particles after the addition of complement (C). Human peripheral blood mononuclear leukocytes (MNLs) also lysed the antibody-coated, infected HuFs. Lymphocytes formed broad-based areas of attachment to the antiHSV-treated cells. Beneath these areas of contact occurred focal cytoplasmic changes that preceded cell lysis. Monocytes showed multiple points of binding and sent cytoplasmic projections over the surface of the infected HuFs. Virus particles and segments of target cell cytoplasm were gathered into vacuoles of the monocyte. In accord with the above morphologic findings, the relative roles that antibody, C, and leukocytes may play in human viral diseases is discussed.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1994

Different signaling pathways for CD18-mediated adhesion and Fc-mediated phagocytosis. Response of neutrophils to LPS.

The regulation of CD11b/CD18 adhesive and phagocytic functions on human polymorphonuclear leukocytes (PMN) in response to LPS was examined. Adhesion of PMN to surfaces coated with LPS had little or no effect on the cells, but pretreating the LPS-coated surfaces with either diluted serum or LPS-binding protein strongly enhanced their ability to bind C3bi-coated E (EC3bi), a ligand for CD11b/CD18. LPS-binding protein is known to enable responses of cells to LPS by facilitating binding of LPS to CD14. Consistent with this, we found that preformed complexes of LPS with soluble rCD14 stimulated binding of ligand by CD11b/CD18 in a concentration-dependent manner. Known agonists that stimulate CD11b/CD18 binding activity on PMN all cause simultaneous enhancement of Fc-mediated phagocytosis. However, LPS presented in complex with either serum proteins or CD14 failed to stimulate the ingestion of ElgG by PMN. The number of FcRs and their ability to bind ligand were not affected by treatment with LPS, nor were they compromised in their ability to respond to other agonists. These results suggest that LPS generates intracellular signals that alter the ability of CD11b/CD18 to bind ligand, but this alteration is not sufficient to promote phagocytosis of IgG-coated particle. This conclusion was confirmed by showing that PMN treated with LPS and serum produced a lipid with the properties of integrin-modulating factor 1: acetone extracts of these cells stimulated CD11b/CD18 adhesive capacity on PMN. However, the lipid did not enhance Fc-mediated phagocytosis. These studies suggest that CD14 affects CD11b/CD18 function by inducing the synthesis of a lipid such as IMF-1, and that this lipid affects only the binding activity, not the phagocytosis-promoting capacity of CD11b/CD18.

Antigens, CD↗
PubMed1994

gamma-Aminobutyric acid receptor-mediated regulation of periventricular-hypophysial dopaminergic neurons: possible role in mediating stress- and 5-hydroxytryptamine-induced decreases in neuronal activity.

The present study examined the effects of gamma-aminobutyric acid (GABA) agonists and antagonists on basal periventricular-hypophysial dopaminergic (PHDA) neuronal activity with a focus on the role of endogenous GABA in mediating 5-hydroxytryptamine- and stress-induced decreases in PHDA neuronal activity. PHDA neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in terminals of these neurons in the intermediate lobe of the pituitary. Plasma concentrations of alpha-melanocyte-stimulating hormone (alpha MSH) also were determined to provide a further index of PHDA neuronal activity. Administration of the GABAB agonist baclofen, but not the GABAA agonist isoguvacine, produced dose- and time-related decreases in intermediate lobe DOPAC concentrations and corresponding increases in plasma alpha MSH concentrations. Administration of either the GABAA antagonist SR-95,531 [2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)-pyridazinium bromide] or GABAB antagonists 2-hydroxysaclofen and CGP-35,348 [P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid; SR-95-531 did not alter basal intermediate lobe DOPAC concentrations or plasma alpha MSH concentrations per se, indicating that endogenous GABA does not tonically inhibit PHDA neuronal activity or alpha MSH secretion. 2-Hydroxysaclofen and CGP-35,348 did, however, reverse the baclofen-induced decrease in intermediate lobe DOPAC concentrations and increase in plasma alpha MSH concentrations. In a similar fashion, 2-hydroxysaclofen blocked the inhibitory effects of stress and the 5-hydroxytryptamine2/1c receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane] on PHDA neuronal activity. These results indicate that GABAB and not GABAA receptor activation inhibits basal PHDA neuronal activity, and that GABAB receptor activation mediates the inhibitory effects of 5-hydroxytryptamine and stress on PHDA neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Mediator release from mast cells by nerve growth factor. Neurotrophin specificity and receptor mediation.

Nerve growth factor causes mediator release from rat peritoneal mass cells in the presence of lysophosphatidylserine. We have investigated the neurotrophin and receptor specificity involved in this response. Nerve growth factor produced a dose-dependent release of [14C]serotonin in the presence of lysophosphatidylserine with an EC50 of approximately 1 nM. Incubation with brain-derived neurotrophic factor and neurotrophin-3 did not produce a response. Northern blot analysis with probes for low affinity nerve growth factor receptor (p75), trkA, trkB, and trkC demonstrated a detectable signal for trkA only. Western blots of trkA immunoprecipitates from mast cell culture lysates, probed with anti-phosphotyrosine antibodies, demonstrated expression of functional TrkA protein. To determine whether p75, trkB, or trkC mRNA was present in amounts below the limit of detection for Northern analysis, a sensitive reverse transcriptase polymerase chain reaction protocol was used; again rat peritoneal mast cells demonstrated only trkA. The predominant form of trkA message expressed in rat peritoneal mast cells was smaller than the neuronal form. An 18-nucleotide exon (coding for 6 amino acids in the extracellular domain) in the neuronal message was not found in the predominant mast cell trkA message. PC12 cells, a rat pheochromocytoma cell line, and dissociated rat sympathetic neurons showed both trkA and p75, but not trkB or trkC. Anterior pituitary expressed both trkB and trkC, but not trkA. To confirm the lack of expression of p75 on mast cells, 125I-nerve growth factor was chemically cross-linked to mast cells or PC12 cells and then immunoprecipitated with a monoclonal antibody specific for p75, 192-IgG; no p75 was detected. Thus, mediator release from rat peritoneal mast cells by nerve growth factor was specific and not a general property of neurotrophins, and the response was modulated through the trkA proto-oncogene. To our knowledge, this is the first description of a bone marrow-derived cell type that expresses trkA at both the mRNA and protein levels. These data provide further evidence that p75 is not necessary for nerve growth factor signal transduction.

Animals↗
PubMed1996

A potential mechanism for proximal tubule angiotensin II-mediated sodium flux associated with receptor-mediated endocytosis and arachidonic acid release.

Angiotensin II (Ang II) receptors in the proximal nephron significantly affect renal salt and water reabsorption. The predominant tubular-epithelial cell Ang II receptor, type 1 Ang II receptors (AT1R), is a member of the superfamily of G-protein-coupled receptors. Tubular cell AT1R are unusual as they are polarized to apical (AP) and basolateral (BL) cell membranes. In a proximal tubule cell model that mimics the in vivo polar distribution of AT1R (LLC-PKC14 cells transfected with rabbit AT1R), we have determined that AP and BL AT1R display differential rates of endocytosis and recycling. In addition, AP AT1R recycling was selectively inhibited by quinacrine, a non-specific inhibitor of phospholipase A2 (PLA2) activity and HELSS, a mechanism-based inhibitor of calcium-independent PLA2 activity. PLA2 catalyzes the hydroysis of sn-2 fatty acyl bonds, liberating free fatty acids and lysophosphoslipids, and proximal tubule AT1R are known to couple to PLA2 as a signaling pathway. In this model, AP Ang II treatment selectively stimulated [3H]-arachidonic acid ([3H]-AA) release. Furthermore, inhibiting AP AT1R endocytosis+recycling with either phenylarsine oxide (PAO) or HELSS, decreased AP Ang II-stimulated [3H]-AA release. In other studies, Ang II internalization also has been linked to vectorial sodium (Na+) flux. Preliminary studies in our model also suggested that HELSS inhibited AP Ang II-stimulated Na+ flux (AP --> BL), raising the possibility that AP AT1R targeting in proximal tubular epithelium, the endocytic profile of these receptors, and AP AT1R-mediated arachidonic acid release combine to serve as additional contributors to Ang II-mediated Na+ flux in the nephron.

Angiotensin II↗
PubMed1997

Apolipoproteins of HDL can directly mediate binding to the scavenger receptor SR-BI, an HDL receptor that mediates selective lipid uptake.

The class B type I scavenger receptor, SR-BI, binds HDL, mediates selective uptake of HDL cholesteryl esters by cultured cells, and its expression is coordinately regulated with steroidogenesis in several endocrine tissues (adrenal, ovary, testes). SR-BI can also bind LDL and anionic phospholipids, which raised the possibility that HDL apolipoproteins might not participate directly in HDL binding. We have examined the ability of individual human HDL apolipoproteins (apoA-I, apoA-II, and apoC-III) reconstituted into phospholipid/unesterified cholesterol complexes to bind to murine SR-BI (mSR-BI) expressed in stably transfected cultured cells. All three apolipoprotein/phospholipid/unesterified cholesterol complexes specifically associated with mSR-BI expressing cells with high affinity and competed for the binding of HDL, while apolipoprotein-free complexes did not. Furthermore, lipid-free forms of these soluble apolipoproteins also competed for HDL and apolipoprotein/ phospholipid/cholesterol complex association with mSR-BI, but locust high density lipophorin and bovine serum albumin were not effective competitors.Thus, all three of the HDL apolipoproteins (apoA-I, apoA-II, and apoC-III) tested can directly mediate binding to mSR-BI, and this multiligand apolipoprotein receptor may be responsible for at least some of the multilipoprotein and apolipoprotein binding activity previously observed in cells and tissues.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Chitin particle-induced cell-mediated immunity is inhibited by soluble mannan: mannose receptor-mediated phagocytosis initiates IL-12 production.

Previous studies showed that mouse spleen cells produced IL-12, TNF-alpha, and IFN-gamma when stimulated with phagocytosable-size chitin particles (N-acetyl-D-glucosamine polymers). To dissect the mechanisms of the cytokine production in this study, spleen cells from BALB/c mice were cultured with 1 to 10 microm chitin particles, heat-killed Corynebacterium parvum vaccine, zymosan, and mannan (a mannose polymer)-coated latex beads (1 microm) at 1, 10, or 100 microg/ml. We found that these particles induced IL-12, TNF-alpha, and IFN-gamma. However, these cytokines were not produced when spleen cells were cultured with soluble chitin, mannan, or laminarin (a polymer of beta-glucan), 1 to 10 microm beta-glucan particles, laminarin-coated latex beads, 1 microm latex beads, 50 to 100 microm chitin particles, or 50 to 100 microm mannan-coated beads. Soluble mannan, but not soluble laminarin, inhibited cytokine production following stimulation with 1 to 10 microm chitin particles, zymosan, or heat-killed C. parvum. In addition, cytochalasin D also inhibited cytokine production. The treatments with soluble mannan or with cytochalasin D, in sharp contrast, did not inhibit LPS-induced IL-12/IFN-gamma production or exogenous IL-12-induced IFN-gamma production. Finally, spleen cells from C3H/HeJ mice also showed comparable levels of IL-12/TNF-alpha/IFN-gamma production when induced by 1 to 10 microm chitin particles. Taken together, our results indicate that mannose receptor-mediated phagocytosis, but not the receptor-mediated pinocytosis, is highly associated with the production of IFN-gamma-inducing extracellular signaling factors such as IL-12 and TNF-alpha. The novel mechanism of phagocytosis-dependent IL-12 production appears to be distinct from that of LPS-induced cytokine production.

Actins↗
PubMed1997

Cholesterol efflux mediated by apolipoproteins is an active cellular process distinct from efflux mediated by passive diffusion.

It is becoming increasingly accepted that removal of cellular cholesterol occurs by at least two pathways, one involving the well-described aqueous diffusion mechanism and another promoted by lipid-free apolipoproteins. We compared the contribution of apolipoprotein-dependent and -independent pathways, taking into consideration the influence of cellular metabolism, on cholesterol efflux promoted by different extracellular acceptor types. The acceptors used were assumed to participate in only passive efflux by lipid-dependent mechanisms (phospholipid vesicles and trypsin-modified high density lipoproteins) or to stimulate efflux by apolipoprotein-dependent pathways (purified apolipoprotein A-I and high density lipoproteins). Apolipoprotein-mediated cholesterol efflux was only apparent in growth-arrested or cholesterol-enriched cells and required metabolic energy. In contrast, cholesterol efflux by apolipoprotein-depleted acceptors did not depend on cell growth state, cholesterol enrichment, or metabolic energy. Apolipoprotein-mediated efflux was not observed at temperatures below 22 degrees C, while apolipoprotein-independent efflux was only reduced by 50% at 4 degrees C compared with incubations at 37 degrees C. Additionally, apolipoproteins promoted a more rapid and larger decrease in intracellular cholesteryl esters when measured by changes in cholesteryl ester radioactivity, mass, or the pool of cholesterol available for esterification by acyl coenzyme A:cholesterol acyltransferase. Efflux of excess cellular cholesterol by an apolipoprotein-dependent pathway appears to involve specific cellular events consistent with the properties of an active transport pathway and distinguishable from cholesterol efflux by apolipoprotein-depleted acceptors through passive mechanisms.

Apolipoprotein A-I↗
PubMed2004

Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators.

Urotensin-II (U-II), the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic G(q)-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its G(q)-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor "unmasked" U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202+/-8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC(50) 0.7+/-0.2 nM) and [(3)H]-leucine incorporation (EC(50) 150+/-40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy ( K(B) 34+/-6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1-beta is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure.

Animals↗
PubMed2005

MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription.

Human TRAP/Mediator is a key coactivator for many transcription factors that act through direct interactions with distinct subunits, and MED1/TRAP220 is the main subunit target for various nuclear receptors. Remarkably, the current study shows that MED1/TRAP220 only exists in a TRAP/Mediator subpopulation (less then 20% of the total) that is greatly enriched in specific TRAP/Mediator subunits and is tightly associated with a near stoichiometeric level of RNA polymerase II. Importantly, this MED1/TRAP220-containing holoenzyme supports both basal- and activator-dependent transcription in an in vitro system lacking additional RNA polymerase II. Furthermore, chromatin immunoprecipitation experiments demonstrate an activator-selective recruitment of MED1/TRAP220-containing versus MED1/TRAP220-deficient TRAP/Mediator complexes to estrogen receptor (ER) and p53 target genes, respectively. Finally, RNAi studies show that MED1/TRAP220 is required for ER-mediated transcription and estrogen-dependent breast cancer cell growth. These observations have significant implications for our current understanding of the composition, heterogeneity, and functional specificity of TRAP/Mediator complexes.

Breast Neoplasms↗
PubMed2006

Herpes virus entry mediator synergizes with Toll-like receptor mediated neutrophil inflammatory responses.

In microbial infections polymorphnuclear neutrophils (PMN) constitute a major part of the innate host defence, based upon their ability to rapidly accumulate in inflamed tissues and clear the site of infection from microbial pathogens by their potent effector mechanisms. The recently described transmembrane receptor herpes virus entry mediator (HVEM) is a member of the tumour necrosis factor receptor super family and is expressed on many haematopoietic cells, including T cells, B cells, natural killer cells, monocytes and PMN. Interaction of HVEM with the natural ligand LIGHT on T cells has a costimulatory effect, and increases the bactericidal activity of PMN. To further characterize the function of HVEM on PMN, we evaluated the effect of receptor ligation on human PMN effector functions using an agonistic monoclonal antibody. Here we demonstrate that activation of HVEM causes activation of neutrophil effector functions, including respiratory burst, degranulation and release of interleukin-8 in synergy with ligands for Toll-like receptors or GM-CSF. In addition, stimulation via HVEM enhanced neutrophil phagocytic activity of complement opsonized, but not of non-opsonized, particles. In conclusion, these results indicate a new, as yet unknown, participation of HVEM in the innate immune response and points to a new link between innate and adaptive immunity.

Cell Degranulation↗