Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material

The expression and cellular localization of angiotensin II (Ang II) and AT(1) receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT(1) receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4+/-0.2%, n=5 vs. BPH: 22.7+/-1.9%, n=5, p<0.001). However, AT(1) receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4+/-2.2%, n=4 vs. BPH: 9.4+/-1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT(1) receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functions on cellular growth and smooth muscle tone in the human prostate. Furthermore, AT(1) receptor down-regulation in BPH may be due to receptor hyperstimulation by increased local levels of Ang II in BPH. These data extend previous findings in support of the novel concept that overactivity of the renin-angiotensin system (RAS) may be involved in the pathophysiology of BPH.     

Chronic Cocaine Injections Attenuate Behavioral Response of κ-Opioid Receptors to U-50,488H Agonist

Chronic injections of cocaine (20 mg/kg daily for 10 days) increase activity and decrease anxiety in male C57Bl/6j mice in comparison with animals chronically injected with normal saline. U-50,488H (κ-opioid receptor agonist; 2.5 mg/kg) produced an anxiolytic effect in animals preinjected with normal saline and had no effect in animals chronically injected with cocaine. Presumably, chronic activation of dopaminergic systems caused by cocaine injections is paralleled by desensitization of k-opioid receptor system. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 140, No. 9, pp. 305–307, September, 2005     

Recent developments in molecular action of antihormones

 Antihormones are by definition antagonists of steroid hormone action. They interact with the ligand binding domains of steroid hormone receptors and competitively inhibit the action of the receptors by mechanisms that are not quite understood. In certain cases antihormones also exhibit agonistic activity especially in connection with certain naturally occurring receptor mutants. These observations together with findings of indiscriminate interaction of antihormones with several classes of steroid receptors have necessitated a search of more effective and reliable antihormones. Recent advances in the resolution of the crystal structure of the ligand binding domains of certain members of the steroid receptor family and identification of non-liganded activation of steroid receptors have produced considerable information that can be harnessed into a fruitful search for a new generation of antihormones. Received: 19 June 1997 / Accepted: 10 October 1997     

T cell stimulation in the absence of exogenous antigen: a T cell signal is induced by both MHC-dependent and -independent mechanisms

Mature T cells residing in peripheral lymphoid organs have frequent contact with antigen presenting cells (APC). Such contact may be required for T cell survival, but the degree to which signals in mature T cells are induced by TCR recognition of self peptide/MHC complexes is unclear. We have used induction of the early growth response gene 1 (Egr1) as an indicator of signal transduction in 3.L2 (I-Ek-restricted) T cells interacting with APC in the absence of exogenous antigen. The data show that Egr1 can be induced in 3.L2 T cells by TCR recognition of self peptides presented by I-Ek. However, a more transient induction of Egr1 can be induced in 3.L2 T cells interacting with dendritic cells derived from class II/beta2m double-deficient mice. Egr1 induction after T cell-APC contact was also observed in a freshly isolated polyclonal CD4 T cell population. The data suggest that self peptide/MHC recognition by the TCR induces a signal in T cells and that dendritic cells can also induce a more transient T cell signal by an MHC-independent mechanism.     

Dendritic cells and natural killer cells in the pathogenesis of HIV infection

Dendritic cells (DC) and natural killer (NK) cells, the main cellular components of the innate immune system, participate in the most ancient first line of defense against infections. Both types of cells patrol peripheral tissues, whereas their rapid recruitment and activation at mucosal surfaces [the major entry point for the human immunodeficiency virus (HIV)] is a hallmark of acute inflammatory response. The ability of HIV to survive and replicate in the human host relies upon several molecular mechanisms eluding the immune surveillance of both adaptive immunity and of DC and NK cells beginning with the acute phase of primary HIV infection. DC and NK cells, unlike CD4⁺ T cells, are impaired more functionally rather than being depleted by HIV infection. In this article we will review some of the aspects of DC/NK cells interaction with HIV infection both in vitro and in vivo, and we will also speculate on the potential consequence for HIV pathogenesis and for the capacity of the virus to escape the surveillance of the innate immune system.     

Chemosensory Cell-Derived Acetylcholine Drives Tracheal Mucociliary Clearance in Response to Virulence-Associated Formyl Peptides

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Modulation of receptors for the colony-stimulating factor, CSF-1, by bacterial lipopolysaccharide and CSF-1

The ability of the mononuclear phagocyte-specific colony-stimulating factor, CSF-1, to down-regulate its receptor on peritoneal exudate macrophages (PEM) was examined. Because of the essentially irreversible binding of CSF-1 to its receptor at 2 degrees C, unoccupied cell surface receptors could be measured by rapidly cooling PEM to 2 degrees C and determining the amount of 125I-CSF-1 bound at this temperature. On incubation with 125I-CSF-1 at 37 degrees C more receptors were lost than could be accounted for by 125I-CSF-1 binding. This receptor loss, apparently caused by CSF-1 itself, was shown to be due in large part to the presence of contaminating lipopolysaccharide (LPS), which at 10 ng/ml was by itself able to cause complete loss of the CSF-1 receptors. LPS also induced loss of the insulin receptor by PEM. LPS did not cause apparent CSF-1 receptor loss by binding to the receptor or by stimulating the release of CSF-1 or substances which compete for the binding of 125I-CSF-1 to the receptor. However, LPS did stimulate release of factors by LPS responsive (C3H/HeN) PEM which caused CSF-1 receptor loss by LPS non-responsive (C3H/HeJ) PEM. In the absence of LPS induced effects, incubation of 125I-CSF-1 with PEM at 37 degrees C resulted in down-regulation of the CSF-1 receptors. The number of CSF-1 receptor sites down-regulated corresponded to the number of CSF-1 molecules that were cell-associated plus the number that were intracellularly degraded and released.     

Platelet-derived growth factor (PDGF) BB acts as achemoattractant for human malignant mesotheliomacells via PDGF receptor b - integrin a3b1 interaction

Platelet-derived growth factor BB (PDGF BB) and the PDGF receptor b are expressed on mesotheliomacells, but their biological function has not yet been defined. In the present study we used Boyden chambersfitted with filters coated with the adhesive matrix proteins fibronectin, laminin, collagen type IV or the non-matrixadhesive molecule poly-L-lysine (PLL). Mesothelioma cells migrated towards PDGF BB at concen-trationsranging from 0.78 to 12.5 ng/ml if matrix proteins were present as adhesive substrates. This migrationwas integrin dependent since the same cells failed to migrate if the adhesive interactions necessary for migra-tionwere provided by molecules other than integrins. Migration of mesothelioma cells on fibronectin, lamininor collagen-type IV in response to PDGF BB was inhibited if the cells were pretreated with blocking anti-bodiesto a3b1 integrin. These findings describe for the first time PDGF BB as a chemoattractant for malig-nantmesothelioma cells and that collaboration between PDGF receptor b and integrin a3b1 is necessaryfor the motile response of these cells to PDGF BB.©Kluwer Academic Publishers     

Differential sensitivity to Arg side chain modification of IL-1β binding to type I and type II receptors

The central role of interleukin-1 (IL-1) in several disease processes, including fever and inflammation, makes the characterization of ligand-receptor interaction of prime importance.The role of arginine (Arg) side chains of hr-IL-1 in receptor recognition was studied by the modification of Arg residues with the specific reagent 1,2-cyclohexanedione. It was found that chemical modification of Arg residues decreased the binding potential of IL-1 to type I receptor dramatically (by 230-fold) while the affinity to type II receptor was reduced only moderately (by 10-fold), with an insignificant reduction of the dissociation rate.These studies suggest that intact Arg side chains of IL-1 may be necessary for high affinity binding to type I IL-1 receptor, but have less importance for the interaction of IL-1 with type II IL-1 receptor.This observation may be useful in the study of type II IL-1 receptor-mediated biological responses and design of receptor-subtype specific ligands as well.     

The control of chloride conductance in rat parotid isolated acinar cells investigated by photorelease of caged compounds

The control of Cl^– conductance in rat parotid isolated acinar cells was studied by combined use of whole-cell recording and flash photolysis techniques. Cells were voltage-clamped either at a membrane potential of –40 mV or stepped between –85 mV and 0 mV. Bath-applied carbachol and noradrenaline evoked Cl^– current at –85 mV and K⁺ current at 0 mV. Similar current activations resulted from the photolytic release of either inositol trisphosphate (InsP ₃) or Ca²⁺ by a brief near-UV flash. The peak amplitudes of the Cl^– conductance (at –85 mV), measured relative to the K⁺ conductance (at 0 mV), evoked by application of carbachol, noradrenaline or direct manipulation of cytosolic free calcium ([Ca²⁺]_i), were very similar, being 0.56±0.09 (mean±SEM,n=9), 0.52 ± 0.01 (n=7) and 0.46±0.06 (n=7). In contrast, the relative amplitude of the Cl^– conductance evoked by InsP₃ was much larger: 1.49±0.24 (n=9). Neither bath application of isoprenaline nor photolysis of caged cAMP induced any detectable membrane current. The most probable interpretation of these results is that the observed activation of Cl^– conductance by agonists can be explained by the elevation of [Ca²⁺]_i alone. In addition, the present results provide further support for the previously reported suggestion that the Cl^– channels and the Ca²⁺-release sites are co-localised [10].