Cells Of High Endothelial Venules Research Articles

PD02-11 THE EXTENT OF CHRONIC PROSTATIC INFLAMMATION WAS NEGATIVELY AND POSITIVELY CORRELATED WITH THE DURATION OF ALPHA-1 BLOCKERS AND 5 ALPHA REDUCTASE INHIBITORS BEFORE SURGICAL TREATMENT

You have accessJournal of UrologyCME1 Apr 2023PD02-11 THE EXTENT OF CHRONIC PROSTATIC INFLAMMATION WAS NEGATIVELY AND POSITIVELY CORRELATED WITH THE DURATION OF ALPHA-1 BLOCKERS AND 5 ALPHA REDUCTASE INHIBITORS BEFORE SURGICAL TREATMENT So Inamura, Tomochika Shinagawa, Hisato Kobayashi, Manami Tsutsumiuchi, Masaya Seki, Minekatsu Taga, Masato Fukushima, Osamu Yokoyama, and Naoki Terada So InamuraSo Inamura More articles by this author , Tomochika ShinagawaTomochika Shinagawa More articles by this author , Hisato KobayashiHisato Kobayashi More articles by this author , Manami TsutsumiuchiManami Tsutsumiuchi More articles by this author , Masaya SekiMasaya Seki More articles by this author , Minekatsu TagaMinekatsu Taga More articles by this author , Masato FukushimaMasato Fukushima More articles by this author , Osamu YokoyamaOsamu Yokoyama More articles by this author , and Naoki TeradaNaoki Terada More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Alpha 1 blockers (ABs) and 5 alpha-reductase inhibitors (5ARIs) have been used for the medical treatment of benign prostatic hyperplasia (BPH) and the patients resistant to these therapies receive surgical treatment. We previously reported that the extent of chronic prostatic inflammation was positively correlated with the obstruction of BPH patients in pressure flow study (Inamura et al. Prostate 2018). This study investigated the correlation of the duration of ABs and 5ARIs with the extent of chronic inflammation by evaluating the expression levels of high endothelial venule (HEV) in prostate tissue. METHODS: Tissue samples were obtained from BPH patients who underwent transurethral resection of the prostate (TURP) or holmium enucleation of the prostate (HoLEP). All the patients received pressure flow study before the surgery. HEV is associated with the migration of lymphocytes and is used as a marker of chronic inflammation. The magnitude of prostatic inflammation was quantified histologically by the ratio of HEV and endothelial cells using the immunohistochemistry of MECA-79 and CD34. The type and duration of medical treatment before surgery were examined on medical records. The correlation of MECA-79/CD34 ratio with the duration of ABs and 5ARIs was evaluated. RESULTS: In 148 patients, 143 patients (97%) received ABs and 33 patients (22%) received 5ARIs adding to ABs. The median duration ABs was 14 months, and the median duration of 5ARIs was 7 months. The duration of ABs was significantly negatively correlated with Bladder Outlet Obstruction Index (BOOI) in pressure flow study (correlation coefficient=-0.270 p=0.029). The duration of ABs was significantly negatively correlated with MECA-7/CD34 ratio (correlation coefficient=-0.194, p=0.030). However, the duration of 5ARIs was positively correlated with MECA-7/CD34 ratio (correlation coefficient=0.501, p=0.001). CONCLUSIONS: These results indicated that the patients who received longer treatment by ABs before surgery had lower level of obstruction and lower extent of chronic prostatic inflammation. However, the patients who received longer treatment of 5ARIs had higher extent of chronic prostatic inflammation. The long-term therapy by 5ARIs might have potential to enhance chronic inflammation in prostate tissue. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e72 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information So Inamura More articles by this author Tomochika Shinagawa More articles by this author Hisato Kobayashi More articles by this author Manami Tsutsumiuchi More articles by this author Masaya Seki More articles by this author Minekatsu Taga More articles by this author Masato Fukushima More articles by this author Osamu Yokoyama More articles by this author Naoki Terada More articles by this author Expand All Advertisement PDF downloadLoading ...

Stepwise transmigration of T- and B cells through a perivascular channel in high endothelial venules.

High endothelial venules (HEVs) effectively recruit circulating lymphocytes from the blood to lymph nodes. HEVs have endothelial cells (ECs) and perivascular sheaths consisting of fibroblastic reticular cells (FRCs). Yet, post-luminal lymphocyte migration steps are not well elucidated. Herein, we performed intravital imaging to investigate post-luminal T- and B-cell migration in popliteal lymph node, consisting of trans-EC migration, crawling in the perivascular channel (a narrow space between ECs and FRCs) and trans-FRC migration. The post-luminal migration of T cells occurred in a PNAd-dependent manner. Remarkably, we found hot spots for the trans-EC and trans-FRC migration of T- and B cells. Interestingly, T- and B cells preferentially shared trans-FRC migration hot spots but not trans-EC migration hot spots. Furthermore, the trans-FRC T-cell migration was confined to fewer sites than trans-EC T-cell migration, and trans-FRC migration of T- and B cells preferentially occurred at FRCs covered by CD11c+ dendritic cells in HEVs. These results suggest that HEV ECs and FRCs with perivascular DCs delicately regulate T- and B-cell entry into peripheral lymph nodes.

Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges

Summary Hevin is secreted by astrocytes and its synaptogenic effects are antagonized by the related protein, SPARC. Hevin stabilizes neurexin-neuroligin transsynaptic bridges in vivo. A third protein, membrane-tethered MDGA, blocks these bridges. Here, we reveal the molecular underpinnings of a regulatory network formed by this trio of proteins. The hevin FS-EC structure differs from SPARC, in that the EC domain appears rearranged around a conserved core. The FS domain is structurally conserved and it houses nanomolar affinity binding sites for neurexin and neuroligin. SPARC also binds neurexin and neuroligin, competing with hevin, so its antagonist action is rooted in its shortened N-terminal region. Strikingly, the hevin FS domain competes with MDGA for an overlapping binding site on neuroligin, while the hevin EC domain binds the extracellular matrix protein collagen (like SPARC), so that this trio of proteins can regulate neurexin-neuroligin transsynaptic bridges and also extracellular matrix interactions, impacting synapse formation and ultimately neural circuits.

Myo1e modulates the recruitment of activated B cells to inguinal lymph nodes.

The inclusion of lymphocytes in high endothelial venules and their migration to the lymph nodes are critical steps in the immune response. Cell migration is regulated by the actin cytoskeleton and myosins. Myo1e is a long-tailed class I myosin and is highly expressed in B cells, which have not been studied in the context of cell migration. By using intravital microscopy in an in vivo model and performing in vitro experiments, we studied the relevance of Myo1e for the adhesion and inclusion of activated B cells in high endothelial venules. We observed reduced expression of integrins and F-actin in the membrane protrusions of B lymphocytes, which might be explained by deficiencies in vesicular trafficking. Interestingly, the lack of Myo1e reduced the phosphorylation of focal adhesion kinase (FAK; also known as PTK2), AKT (also known as AKT1) and RAC-1, disturbing the FAK-PI3K-RAC-1 signaling pathway. Taken together, our results indicate a critical role of Myo1e in the mechanism of B-cell adhesion and migration.

Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

Chikungunya virus (CHIKV) causes acute and chronic rheumatologic disease. Pathogenic CHIKV strains persist in joints of immunocompetent mice, while the attenuated CHIKV strain 181/25 is cleared by adaptive immunity. We analyzed the draining lymph node (dLN) to define events in lymphoid tissue that may contribute to CHIKV persistence or clearance. Acute 181/25 infection resulted in dLN enlargement and germinal center (GC) formation, while the dLN of mice infected with pathogenic CHIKV became highly disorganized and depleted of lymphocytes. Using CHIKV strains encoding ovalbumin-specific TCR epitopes, we found that lymphocyte depletion was not due to impaired lymphocyte proliferation. Instead, the accumulation of naive lymphocytes transferred from the vasculature to the dLN was reduced, which was associated with fewer high endothelial venule cells and decreased CCL21 production. Following NP-OVA immunization, NP-specific GC B cells in the dLN were decreased during pathogenic, but not attenuated, CHIKV infection. Our data suggest that pathogenic, persistent strains of CHIKV disable the development of adaptive immune responses within the dLN.

IL-36γ promotes a local immune response via the formation of tertiary lymphoid structures in colorectal carcinoma.

Abstract Tertiary lymphoid structures (TLS) form at sites of chronic inflammation, and locally prime the immune system independently of secondary lymphoid organs. The intratumoral presence of TLS has been associated with a positive prognostic outcome for patients with solid tumors, including colorectal carcinoma. Thus, the therapeutic induction of TLS would be hypothesized to confer clinical benefit to patients. Indeed, the therapeutic introduction of the IL-1 family cytokine IL-36 gamma into the tumor microenvironment (TME) of murine MC38 colon carcinoma leads to delayed tumor progression and the development of TLS at 5 days post-treatment. The TLS present with characteristics of secondary lymphoid organs, including PNAd+ high endothelial venules (HEV) surrounded by CD3+ T cells and CD11c+ dendritic cells, but are considered as “non-classical” due to the absence of a defined B cell zone. The formation of TLS is dependent upon the adaptive immune response, as IL-36 gamma-treated tumors grown in Rag2−/− animals fail to present with PNAd+ vasculature within the tumor. Thus, crosstalk between the immune system and cells of the vasculature is key to the efficacy of the IL-36 gamma-induced anti-tumor immune response. In human colorectal carcinoma, IL-36 gamma was also observed to promote the local anti-tumor immune response. Expression of IL-36 gamma by vascular endothelial cells of HEV was associated with an increased density of CD20+ B cells in TLS. Specific IL-36 gamma production by CD68+ macrophages was associated with an increased infiltration of CD4+ central memory T cells into the TME. Therefore, IL-36 gamma is a pro-inflammatory mediator involved in the anti-tumor immune response in both murine and human colorectal cancer.

The Use of Intravital Two-Photon and Thick Section Confocal Imaging to Analyze B Lymphocyte Trafficking in Lymph Nodes and Spleen.

Intravital two-photon laser scanning microscopy (TP-LSM) has allowed the direct observation of immune cells in intact organs of living animals. In the B cell biology field TP-LSM has detailed the movement of B cells in high endothelial venules and during their transmigration into lymph organs; described the movement and positioning of B cells within lymphoid organs; outlined the mechanisms by which antigen is delivered to B cells; observed B cell interacting with T cells, other cell types, and even with pathogens; and delineated the egress of B cells from the lymph node (LN) parenchyma into the efferent lymphatics. As the quality of TP-LSM improves and as new fluorescent probes become available additional insights into B cell behavior and function await new investigations. Yet intravital TP-LSM has some disadvantages including a lower resolution than standard confocal microscopy, a narrow imaging window, and a shallow depth of imaging. We have found that supplementing intravital TP-LSM with conventional confocal microscopy using thick LN sections helps to overcome some of these shortcomings. Here, we describe procedures for visualizing the behavior and trafficking of fluorescently labeled, adoptively transferred antigen-activated B cells within the inguinal LN of live mice using two-photon microscopy. Also, we introduce procedures for fixed thick section imaging using standard confocal microscopy, which allows imaging of fluorescently labeled cells deep in the LN cortex and in the spleen with high resolution.

Porcine intestinal lymphoid tissues synthesize estradiol

Estradiol (17β-estradiol) is synthesized primarily in the gonads of both sexes and regulates the development and function of reproductive organs. Recently, we reported that intestinal lymphocyte homeostasis is regulated by estradiol synthesized de novo in the endothelial cells of the high endothelial venules (HEVs) of mesenteric lymph nodes and Peyer's patches in mice. This observation prompted us to hypothesize that HEVs of intestinal lymphoid tissues are sites of estradiol synthesis across species. In this study, we examined whether estradiol is synthesized in the intestinal lymphoid tissues of adolescent piglets. Comparisons of estradiol levels in blood and tissue showed that estradiol concentrations in mesenteric lymph nodes and Peyer's patches were significantly higher than the level in serum. Reverse transcription polymerase chain reaction showed that porcine intestinal lymphoid tissues express mRNAs for steroidogenic enzymes (StAR, 17β-Hsd, 3β-Hsd, Cyp17a1, and Cyp19a1), and immunohistochemical results in ilial tissue showed expression of aromatase (CYP19) in Peyer's patch-localized endothelial cells of HEVs. When mesenteric lymph node and Peyer's patch tissues were cultured in vitro, they produced estradiol. Taken together, the results indicate that mesenteric lymph nodes and Peyer's patches are sites of estradiol synthesis in adolescent piglets.

Estradiol Synthesis in Gut-Associated Lymphoid Tissue: Leukocyte Regulation by a Sexually Monomorphic System.

17β-estradiol is a potent sex hormone synthesized primarily by gonads in females and males that regulates development and function of the reproductive system. Recent studies show that 17β-estradiol is locally synthesized in nonreproductive tissues and regulates a myriad of events, including local inflammatory responses. In this study, we report that mesenteric lymph nodes (mLNs) and Peyer's patches (Pps) are novel sites of de novo synthesis of 17β-estradiol. These secondary lymphoid organs are located within or close to the gastrointestinal tract, contain leukocytes, and function at the forefront of immune surveillance. 17β-estradiol synthesis was initially identified using a transgenic mouse with red fluorescent protein coexpressed in cells that express aromatase, the enzyme responsible for 17β-estradiol synthesis. Subsequent immunohistochemistry and tissue culture experiments revealed that aromatase expression was localized to high endothelial venules of these lymphoid organs, and these high endothelial venule cells synthesized 17β-estradiol when isolated and cultured in vitro. Both mLNs and Pps contained 17β-estradiol with concentrations that were significantly higher than those of peripheral blood. Furthermore, the total amount of 17β-estradiol in these organs exceeded that of the gonads. Mice lacking either aromatase or estrogen receptor-β had hypertrophic Pps and mLNs with more leukocytes than their wild-type littermates, demonstrating a role for 17β-estradiol in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase expression, 17β-estradiol content, or steroidogenic capacity in these lymphoid organs.

Clonal Proliferation and Stochastic Pruning Orchestrate Lymph Node Vasculature Remodeling

Lymph node (LN) expansion during an immune response relies on the transient remodeling of its vasculature. Although the mechanisms driving LN endothelial cell division are beginning to be understood, a comprehensive view of LN endothelial cell dynamics at the single-cell level is lacking. Here, we used multicolored fluorescent fate-mapping models to track the behavior of blood endothelial cells during LN expansion upon inflammation and subsequent return to homeostasis. We found that expansion of the LN vasculature relied on the sequential assembly of endothelial cell proliferative units. This segmented growth was sustained by the clonal proliferation of high endothelial venule (HEV) cells, which act as local progenitors to create capillaries and HEV neo-vessels at the periphery of the LN. Return to homeostasis was accompanied by the stochastic death of pre-existing and neo-synthesized LN endothelial cells. Thus, ourfate-mapping studies unravel-at a single-cell level-the complex dynamics of vascular-tree remodeling during LN expansion and contraction.

L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo

AbstractB-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Lymph nodes (LNs) are sites of malignant proliferation and LN enlargement is associated with poor prognosis in the clinics. The LN microenvironment is believed to favor disease progression by promoting CLL cell growth and drug resistance. A better understanding of the mechanisms regulating trafficking of CLL cells to LNs is thus urgently needed. Here, we studied the first step of CLL cell migration to LNs, their interaction with high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation in lymphoid organs. We observed that the density of HEV blood vessels was increased in CLL LNs and that CD20+ CLL cells accumulated within HEV pockets, suggesting intense trafficking. We used intravital imaging to visualize the behavior of human CLL cells within the mouse LN microcirculation, and discovered that CLL cells bind to HEVs in vivo via a multistep adhesion cascade, which involves rolling, sticking, and crawling of the leukemic cells on the endothelium. Functional analyses revealed that the lymphocyte homing receptor L-selectin (CD62L) is the key factor controlling the binding of CLL cells to HEV walls in vivo. Interestingly, L-selectin expression was decreased on CLL cells from patients treated with idelalisib, a phosphoinositide-3-kinase δ inhibitor recently approved for CLL therapy. Interference with L-selectin–mediated trafficking in HEVs could represent a novel strategy to block dissemination of CLL cells to LNs and increase the efficacy of conventional therapy.

Alterations of high endothelial venules in primary and metastatic tumors are correlated with lymph node metastasis of oral and pharyngeal carcinoma

High endothelial venules (HEVs) are special blood vessels in the paracortical region of lymph nodes (LNs) and govern lymphocyte recruitment. LN metastasis has similarity to circulating lymphocytes homing to LNs, but the role of HEVs in the progression of oral and pharyngeal squamous cell carcinoma (OPSCC) is unclear. In this study, we found that HEVs experienced a series of morphological and functional changes during OPSCC progression and were correlated with LN metastasis. In 9 cases of 73 metastatic LNs, tumor emboli were located adjacent to HEVs or just out of the vessels but not lymphatic channels. Gap junctions of tumor cells close to HEVs decreased or disappeared, and gaps were left at contact points where tumor cells attached to the HEVs. Moreover, the proliferation rate of endothelial cells of HEVs was the highest in metastatic LNs. Finally, L-selectin was detected in both primary and metastatic tumors, and it facilitated tumor cells adhering to LNs. In conclusion, our findings suggest that remodeled HEVs are correlated with LN metastasis of OPSCC and play important role in this process by preparing premetastatic soil for cancer cell metastasis.

Blockade but Not Overexpression of the Junctional Adhesion Molecule C Influences Virus-Induced Type 1 Diabetes in Mice

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.

Osteoprotegerin induction in response to microbial infection

Osteoprotegeirn (OPG) is an endogenous decoy receptor for RANKL, which is a cytokine essential for osteoclast differentiation. Lipopolysaccharide (LPS) is known to induce osteoclast formation when injected onto calvaria in mice. Unexpectedly, we observed that mice injected with LPS up-regulate OPG and down-regulate RANKL levels in peripheral blood. In the present study, we examined whether OPG is induced by microbial infection of various kinds, and the sites and significance of OPG production in infected mice. Wild-type mice infected withSalmonella, Staphylococcus, Mycobacteriaor influenza virus showed increase in OPG levels in peripheral blood. We also found that the levels of OPG in serum of human patients infected with M. tuberculosis and M. avium were significantly increased. Moreover, injection of mice with LPS induced OPG production specifically in lymph nodes, especially in high endothelial venule (HEV)cells, but not in other organs. OPG production was suppressed in c-Fos-deficient mice and enhanced in Fra-1 transgenic mice, indicating that OPG production is regulated by AP-1 transcription factors. Loss of OPG in mice did not affect either their survival or Salmonella proliferation in spleen and liver after infection with virulent strains of Salmonella. Interestingly, however, when wild-type mice were infected with an avirulent Salmonella strain, which can induce OPG, osteoclast development was suppressed and bone mineral density was increased. These data reveal for the first time that lymph nodes protect bones from infection-induced bone loss through OPG production.

Prognostic and Predictive Impact of Intra- and Peritumoral Immune Infiltrates

Leukocyte infiltrates into or around tumor cell nests are found in the context of protumorigenic inflammation and anticancer immunosurveillance. Hence, the detailed composition, density, architecture, and function of leukocyte infiltrates must be analyzed to understand their prognostic impact. The ectopic presence within tumors of high endothelial venule cells, which are normally characteristic for secondary lymphoid organs, correlates with a more pronounced infiltration by T lymphocytes and has a positive predictive impact on local advanced breast cancer treated with neoadjuvant chemotherapy. Recent progress in the field indicates that immune infiltrates of the primary tumors, as well as of metastases, are not only independent prognostic biomarkers but can also constitute predictive factors, suggesting that the pretherapeutic immune response can determine the efficacy of conventional chemotherapies. Moreover, accumulating evidence indicates that chemotherapy can stimulate anticancer immune responses coupled with an increased intratumoral lymphoid infiltration, which correlates with tumor mass reduction and patient survival. Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients.

Novel Regulators of Lymphocyte Trafficking across High Endothelial Venules

The physiological recruitment of circulating lymphocytes from the blood into secondary lymphoid tissues is an essential homeostatic mechanism for the immune system because it allows lymphocytes to encounter efficiently both their specific cognate antigen and the regulatory cells with which they need to interact, to initiate, maintain, and terminate immune responses appropriately. This constitutive lymphocyte trafficking is mediated by high endothelial venules (HEVs), which are present in secondary lymphoid tissues other than the spleen. There is growing evidence that lymphocyte trafficking across HEVs involves at least three steps, namely, (i) tethering/rolling, (ii) arrest/firm adhesion/intraluminal crawling, and (iii) transendothelial migration (TEM). Although the mechanisms underlying the first two steps have been determined relatively well, the mechanism regulating TEM is only partially understood. In particular, the molecular mechanism driving lymphocyte movement from the apical to the basolateral surface of the endothelial cells (ECs) of HEVs remains ill defined. This step is crucial for successful lymphocyte extravasation, and is thus an important target for therapeutic intervention in various immunological diseases. Here, we review the molecular mechanisms governing lymphocyte-HEV interactions, and highlight possible roles for two HEV proteins, i.e., nepmucin/CD300g and autotaxin, in lymphocyte TEM.

Targeting of ICAM-1–directed immunoliposomes specifically to activated endothelial cells with low cellular uptake: use of an optimized procedure for the coupling of low concentrations of antibody to liposomes

Targeted delivery of therapeutics to the endothelium is an important goal in the treatment of inflammatory diseases. The aim of this work was to exploit the overexpression of intercellular adhesion molecule-1 (ICAM-1) on activated endothelial cells for the targeting of anti-ICAM-1–coupled immunoliposomes with the intent for further use as drug carriers. Immunoliposomes were prepared from using an optimized method for the coupling of low concentrations of antibody to liposomes, thereby preventing the loss of antibody through the derivatization, extraction, and activation process. This is especially suitable for limiting ligand conjugates that are isolated or synthesized in small quantities, such as monoclonal antibodies (mAbs). To investigate the functionality of the resulting immunoliposomes, the specificity of binding and cellular internalization studies of liposomes, either nonconjugated or conjugated with mAbs to ICAM-1 or to irrelevant IgG to high endothelial venule (HEV) cells, were analyzed by fluorescence microplate spectroscopy at 4 and 37°C. Immunoliposomes specifically directed against ICAM-1 were shown to bind selectively and specifically to tumor necrosis factor alpha–activated endothelial cells in vitro, with minimal cellular internalization. This study provides a novel delivery system that has the potential for targeting therapeutics to inflammatory tissue.

Insulin-like growth factor-I mRNA and peptide are distinctly confined to subtypes of macrophages, antigen-presenting cells, lymphocytes and HEV cells in non-neoplastic human lymph node

Event Abstract Back to Event Insulin-like growth factor-I mRNA and peptide are distinctly confined to subtypes of macrophages, antigen-presenting cells, lymphocytes and HEV cells in non-neoplastic human lymph node Elisabeth Eppler1*, Dominique Oberlin1 and Christian Fellbaum2 1 University of Zürich, Institute of Anatomy, Switzerland 2 Hegau-Klinikum, Institute of Pathology, Germany IGF-I is a potent hormone that stimulates growth and differentiation and inhibits apoptosis in numerous tissues. Preliminary evidence suggests that IGF-I exerts differentiating, mitogenic and restoring activities also in the immune system. The present study investigates the cellular sites of IGF-I mRNA and peptide on archival human lymph node samples by routine staining, in situ hybridisation with an IGF-I probe, and immunohistochemistry with antisera specific for human IGF-I and CD3 (T-lymphocytes), CD20 (B-lymphocytes), CD68 (macrophages), CD21 (follicular dendritic cells, DC), S100 (interdigitating DC) and podoplanin (fibroblastic reticular cells). Numerous cells within the B- and T-cell compartments showed IGF¬I gene and peptide expression the majority of which was identified as macrophages. Solitary follicular DC exhibited IGF-I mRNA and peptide. B-lymphocytes did not contain IGF-I immunoreactive material, while few T-lymphocytes did. Furthermore, IGF-I mRNA and peptide-expressing cells were identified as high endothelial venule (HEV) cells. From this we conclude that the main task of IGF-I in human non-neoplastic lymph node may be autocrine and paracrine regulation of differentiation, stimulation and survival of lymphocytes, antigen-presenting cells and macrophages and differentiation and maintenance of HEV cells, and that the role for IGF-I in formation and sustaining of lymph node structures is more important than thought so far. Keywords: comparative endocrinology Conference: 25th Conference of the European Comparative Endocrinologists, Pécs, Hungary, 31 Aug - 4 Sep, 2010. Presentation Type: Conference Presentation Topic: Comparative endocrinology Citation: Eppler E, Oberlin D and Fellbaum C (2010). Insulin-like growth factor-I mRNA and peptide are distinctly confined to subtypes of macrophages, antigen-presenting cells, lymphocytes and HEV cells in non-neoplastic human lymph node. Front. Endocrinol. Conference Abstract: 25th Conference of the European Comparative Endocrinologists. doi: 10.3389/conf.fendo.2010.01.00008 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Aug 2010; Published Online: 29 Aug 2010. * Correspondence: Dr. Elisabeth Eppler, University of Zürich, Institute of Anatomy, Zürich, Switzerland, elisabeth.eppler@ana.unibe.ch Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Elisabeth Eppler Dominique Oberlin Christian Fellbaum Google Elisabeth Eppler Dominique Oberlin Christian Fellbaum Google Scholar Elisabeth Eppler Dominique Oberlin Christian Fellbaum PubMed Elisabeth Eppler Dominique Oberlin Christian Fellbaum Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Insulin‐like growth factor I messenger RNA and protein are expressed in the human lymph node and distinctly confined to subtypes of macrophages, antigen‐presenting cells, lymphocytes and endothelial cells

Insulin-like growth factor I (IGF-I) is a potent hormone that stimulates growth and differentiation and inhibits apoptosis in numerous tissues. Preliminary evidence suggests that IGF-I exerts differentiating, mitogenic and restoring activities in the immune system but the sites of synthesis of local IGF-I are unknown. Identification of these sites would allow the functional role of local IGF-I to be clarified. The presence of IGF-I in non-immune cells suggests that it acts as a trophic factor, while its occurrence in subtypes of lymphocytes or antigen-presenting cells indicates paracrine/autocrine direct regulatory involvement of IGF-I in the human immune response. The present study investigated the location of IGF-I messenger RNA and protein on archival human lymph node samples by in situ hybridization, immunohistochemistry and double immunofluorescence staining using an IGF-I probe and antisera specific for human IGF-I and CD3 (T lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), CD21 (follicular dendritic cells), S100 (interdigitating dendritic cells) and podoplanin (fibroblastic reticular cells). Numerous cells within the B- and T-cell compartments expressed the IGF-I gene, and the majority of these cells were identified as macrophages. Solitary follicular dendritic cells exhibited IGF-I. A few T lymphocytes, and no B lymphocytes, contained IGF-I immunoreactive material. Furthermore, IGF-I immunoreactive cells outside the follicles that did not react with CD3, CD20, S100 or podoplanin markers were identified as high-endothelial venule (HEV) cells. From this we conclude that the main task of IGF-I in human non-tumoral lymph node may be autocrine and paracrine regulation of the differentiation, stimulation and survival of lymphocytes, antigen-presenting cells and macrophages and the differentiation and maintenance of HEV cells.

Nuclear Interleukin-33 Is Generally Expressed in Resting Endothelium but Rapidly Lost upon Angiogenic or Proinflammatory Activation

Interleukin (IL)-33 is a novel member of the IL-1 family of cytokines that promotes Th2 responses in lymphocytes as well as the activation of both mast cells and eosinophils via the ST2 receptor. Additionally, IL-33 has been proposed to act as a chromatin-associated transcriptional regulator in both endothelial cells of high endothelial venules and chronically inflamed vessels. Here we show that nuclear IL-33 is expressed in blood vessels of healthy tissues but down-regulated at the earliest onset of angiogenesis during wound healing; in addition, it is almost undetectable in human tumor vessels. Accordingly, IL-33 is induced when cultured endothelial cells reach confluence and stop proliferating but is lost when these cells begin to migrate. However, IL-33 expression was not induced by inhibiting cell cycle progression in subconfluent cultures and was not prevented by antibody-mediated inhibition of VE-cadherin. Conversely, IL-33 knockdown did not induce detectable changes in either expression levels or the cellular distribution of either VE-cadherin or CD31. However, activation of endothelial cell cultures with either tumor necrosis factor-alpha or vascular endothelial growth factor and subcutaneous injection of these cytokines led to a down-regulation of vascular IL-33, a response consistent with both its rapid down-regulation in wound healing and loss in tumor endothelium. In conclusion, we speculate that the proposed transcriptional repressor function of IL-33 may be involved in the control of endothelial cell activation.