Eosinophilic pustular folliculitis (EPF) in a patient with HIV infection.

Eosinophilic pustular folliculitis is a chronic, recurrent dermatosis, of unknown etiology, which is histologically characterized by folliculotropic inflammatory infiltrates with admixed eosinophils in the dermis. It has often presented with immunosuppression and especially with HIV-Infection. In the HAART-era, eosinophilic pustular folliculitis has become a rarity. It is often being misdiagnosed as acne vulgaris, rosacea, bacterial folliculitis, dermatomycosis and seborrheic dermatitis. The treatment of this disease may be difficult.

LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro.

Since the molecular identification of the low density lipoprotein receptor (LDLR), an ever increasing number of related proteins have been discovered. These receptors belonging to the LDLR family are thought to play key roles in lipoprotein metabolism in a variety of tissues, including the arterial wall. We have discovered that the expression of a 250-kDa mosaic LDLR-related protein, which we termed LR11 for the presence of 11 LDLR ligand-binding repeats, is markedly induced in smooth muscle cells in the hyperplastic intima of animal models used for the study of atherosclerosis. Here, we demonstrate that the human LR11, when overexpressed in hamster cells, binds and internalizes 39-kDa receptor-associated protein (RAP), an in vitro ligand for all receptors belonging to the LDLR family. Furthermore, LR11 binds the apolipoprotein E (apoE)-rich lipoproteins, beta-very low density lipoproteins (VLDLs), with a high affinity similar to that of other members, such as the LDLR and VLDL receptor. RAP and beta-VLDL compete with each other; however, other serum lipoproteins are not able to inhibit their binding. LR11 shows specific binding of apoE-enriched HDL prepared from human cerebrospinal fluid as well as of beta-VLDL, suggesting that the apoE content of lipoproteins is most likely important for mediating the high-affinity binding to the receptor. LR11-overexpressing cells are able to internalize and degrade the bound beta-VLDL; these cells also show increased accumulation of cholesteryl esters when incubated with beta-VLDL. Incubation for 48 hours with beta-VLDL of LR11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets. Taken together, LR11, a mosaic LDLR family member whose expression in smooth muscle cells is markedly induced in atheroma, has all the properties of a receptor for the endocytosis of lipoproteins, particularly for the incorporation of apoE-rich lipoproteins.

Differential expression of LR11 during proliferation and differentiation of cultured neuroblastoma cells.

An involvement of the low density lipoprotein receptor (LDLR) gene family in both intracellular signal pathways for neural organization and metabolic pathways for lipoprotein homeostasis is now well established. The discovery of LR11, a mosaic LDLR family member offers the opportunity to gain new insights into receptor multifunctionality. Here, we studied the proliferation-dependent expression of LR11 mRNA and protein using two cultured cell lines, IMR32 neuroblastoma and PC12 pheochromocytoma. Within 24 h, the LR11 protein rose 1.9-fold in proliferating IMR32 cells, and increased further to 5.3-fold at 72 h. This conformed with a transcript level increase of 4.7-fold at 72 h in the proliferating cells. On the other hand, under differentiation conditions, a 2.9-fold increase was observed within 24 h, but at 72 h thereafter the protein levels decreased to 60% of control. The transcript also increased to 1. 8-fold within 24 h, and then decreased to 1.1-fold at 72 h. In order to assess the transcriptional activities of the LR11 gene, we identified the 5'-flanking region of the murine LR11 gene. Transfection of IMR32 and PC12 cells with plasmids containing the whole or deleted fragments of 5'-flanking region showed that element(s) responsible for the above described different transcriptional activities are located in the upstream sequence between -861 and -396. Thus, the transcription of LR11 in these two cell systems is regulated differently during proliferation and differentiation, suggesting that the multifunctionality of LR11, as well as other LDLR family members, for rapid cell growth in malignant cells and neural outgrowth in cultured neurons, respectively. The possible involvement of LR11 in cellular proliferation and differentiation sheds new light on its functions in neurons, malignant, and vascular cells.

The regulatory expression of procollagen COOH-terminal proteinase enhancer in the proliferation of vascular smooth muscle cells.

Intimal hyperplasia following arterial endothelial denudation results in large part from the proliferation of vascular smooth muscle cells (SMCs) and matrix accumulation. Procollagen COOH-terminal proteinase enhancer (PCPE) binds procollagen COOH-propeptides and potentiates procollagen COOH-proteinase activity to cleave COOH-propeptides of procollagens I-III. Here we report the enhanced expression of PCPE in cultured SMCs and in intimal thickening induced by arterial injury. The levels of PCPE mRNA in parallel with the level of p21(Cip1) mRNA, as a negative regulator of cellular proliferation, increased under serum deprivation or reduced cellular proliferation in cultured SMCs. In contrast, rapidly proliferating cells show the decreased levels of PCPE mRNA. In vivo, the marked induction of PCPE in injured rat arteries occurred at 14 days after endothelial denudation. The induced expression levels of PCPE as well as p21(Cip1) were maintained until 42 days, although cyclin E expression declined. Furthermore, transforming growth factor beta1 (TGF-beta1), an important regulator of cellular proliferation in atheroma, increased the levels of the PCPE mRNA in cultured SMCs. Thus, the regulatory expression of PCPE dependent on cellular proliferation, and particularly contact inhibition, may play a key role in the proliferation of SMCs and matrix production during the process of atheroma formation.

Expression of LR11, a mosaic LDL receptor family member, is markedly increased in atherosclerotic lesions.

Receptors belonging to the LDL receptor (LDLR) family are thought to play key roles in lipoprotein metabolism in a variety of tissues, including the arterial wall. Here, we report that the expression of a 250-kDa mosaic LDLR family member, which we called LR11 for the presence of 11 ligand-binding repeats, is markedly induced during the process of atherogenesis in 2 animal models. Analysis by reverse transcription-polymerase chain reaction and RNase protection assays revealed that LR11 transcript levels rise in rabbit aortas displaying atheromatous lesions after the rabbits have been fed a high-cholesterol diet. Immunohistochemistry demonstrated that the highest induction of LR11 occurs in intimal smooth muscle cells (SMCs), followed by medial SMCs close to the intimal border of the atheromatous lesions. Experimental intimal hyperplasia by endothelial denudation showed that LR11 mRNA levels were also increased in the arteries after balloon injury, with the transcripts localized primarily in the hyperplastic intimal layer. In agreement with the correlation of LR11 induction during increased cell proliferation, cultured SMCs showed an increase in LR11 expression in the proliferative phase. Furthermore, Northern and Western blot analyses showed that medium conditioned by the monocyte-macrophage cell line THP-1 enhanced LR11 expression in cultured SMCs. These findings suggest that upregulation of LR11 might be contributing to the pathological roles of intimal and medial SMCs during arteriosclerotic lesion development and provide the first insight into the as yet unknown functional significance of this intriguing LDLR family member.

[Anti-atherogenic drugs].

Rupture of an instable plaque, characterized by a large lipid-rich central core, inflammatory cells, and a thin fibrous cap, causes sudden thrombus formation and acute coronary syndromes (ACS). Lipid lowering therapy by HMG-CoA reductase inhibitors leads to reduction of cardiovascular complications, but has very small effect on the degree of stenosis of ACS. Oxidizing metabolites generated at the site of coronary angioplasty can induce chain reactions that may lead to restenosis. Probucol improves the restenosis rate after coronary angioplasty if given before PTCA (percutaneous transluminal coronary angioplasty). These results will provide a better understanding of drug action, help explain certain drug interactions, and facilitate the choice of a drug for ACS.

Developmental regulation of LR11 expression in murine brain.

Receptors belonging to the low density lipoprotein receptor (LDLR) superfamily play important biological roles in addition to mediating lipoprotein metabolism. The recent discovery of a novel mosaic LDLR family member by us (Yamazaki H., Bujo, H., Kusunoki, J., Seimiya, K., Kanaki, T., Morisaki, N., Schneider, W.J., and Saito, Y. (1996) J. Biol. Chem. 271, 24761-24768) and others, which we termed LR11, offers the opportunity to gain new insights into receptor multifunctionality. The predominant expression of LR11 in brain and the presence of elements found in neural adhesion molecules suggested a function(s) in the central nervous system (CNS). In order to gain information about this complex receptor in an accessible system, we have molecularly characterized the murine LR11 and report on its detailed localization and developmental expression pattern. The primary sequence of the murine protein further establishes that LRlls are among the closest relatives within the LDLR family and that brain is the predominant site of expression. In situ hybridization showed that neuronal bodies such as Purkinje cells in the cerebellum and other neurons in the hippocampal formations and the cerebral cortex are particularly rich in LR11 transcripts. The developmental pattern of LR11 expression in brain, which peaks at 2 weeks, is in contrast to those of two other LDLR family members, the very low density lipoprotein receptor and the LDLR. During early development, murine LR11 expression levels are highly dependent on neural cell types. These findings are compatible with function(s) of LR11 in neural organization and, possibly, pathogenesis of degenerative brain diseases. In addition, detailed knowledge of LR11 biology will help to elucidate the roles of other mosaic proteins that share with LR11 elements whose function is not yet known.

NK-104, a newly developed HMG-CoA reductase inhibitor, suppresses neointimal thickening by inhibiting smooth muscle cell growth and fibronectin production in balloon-injured rabbit carotid artery.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress smooth muscle cell growth and arterial neointimal thickening. In this study, to elucidate the potency and mechanisms of NK-104 ((+)-monocalcium bis[(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate], CAS 147526-32-7) in neointimal thickening, the effect of NK-104 on the neointimal thickening, Br-dU-labeled cell number and extracellular matrix immunohistochemistry were examined in balloon-injured rabbit carotid artery. NK-104 suppressed the neointimal thickening dose-dependently, and the suppression was 69.5% at 1.0 mg/kg. NK-104 suppressed the intimal total and Br-dU-labeled cell number. Fibronectin and type I collagen were observed in 81% and 38% of the total intimal area in the control arteries, respectively, and the areas occupied by fibronectin and type I collagen were significantly decreased by 1.0 mg/kg NK-104 to 39% and 22%, respectively. The decrease in fibronectin per cell was more potently demonstrated. Aortic total and activated TGF-beta contents that were markedly increased in the injured artery were increased further by NK-104. NK-104 concentration-dependently suppressed fibronectin content of the basement lesion in rabbit primary cultured smooth muscle cells. These findings suggest that NK-104 suppresses balloon-injury-induced neointimal thickening through inhibition of intimal smooth muscle cell growth and extracellular matrix accumulation.

A novel mosaic protein containing LDL receptor elements is highly conserved in humans and chickens.

Certain receptors belonging to the LDL receptor (LDLR) gene family appear to constitute a newly identified branch whose members are expressed in brain, in addition to other tissues. In support of this concept, we have now discovered the expression and delineated the molecular structures of a representative of this emerging branch from two such diverse species as human and chicken. This membrane receptor, called LR11 and thus far only known to exist in the rabbit, is a complex seven-domain mosaic protein containing, among other structural elements, a cluster of 11 LDLR ligand-binding repeats and a domain with homology to VPS10, a yeast receptor for vacuolar protein sorting. Cytoplasmic signature sequences define the receptor as competent for endocytosis. The most striking properties of LR11s are their (1) high degree of structural conservation (>80% identity among mammals and birds), with 100% identity in the membrane-spanning and cytoplasmic domains of rabbit and human; (2) lack of regulation by cholesterol and estrogen; and (3) expression in brain. The features of LR11 suggest important roles in intercellular and intracellular ligand transport processes, some of which it may share with other brain-specific LDLR family members.

Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member.

Normal cell development depends to a large part on multifunctional proteins that have evolved by recombination of proven modular elements. We now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotein (LDL) receptor gene family. The extracellular portion of the approximately 250-kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor "YWTD" repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, in particular the hippocampus, dentate gyrus, and cerebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apolipoprotein E-containing lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The identification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunctional mosaic proteins akin to the ever expanding LDL receptor gene family.