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William W Cruikshank - One of the best experts on this subject based on the ideXlab platform.

  • ccr4 t cell recruitment to the skin in mycosis fungoides potential contributions by thymic stromal lymphopoietin and Interleukin 16
    Leukemia & Lymphoma, 2015
    Co-Authors: Marina Tuzova, Keri Chaney, Thomas S. Kupper, Jillian M Richmond, Clara Curiellewandrowski, Deon Wolpowitz, William W Cruikshank
    Abstract:

    Mycosis fungoides (MF) is characterized by skin accumulation of CCR4 � CCR7- eff ector memory T cells; however the mechanism for their recruitment is not clearly identifi ed. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that triggers Th2 immunity and is associated with T cell recruitment to the skin in atopic dermatitis. Interleukin-16 (IL-16) is a chemoattractant and growth factor for CD4 � T cells. We hypothesized that TSLP and IL-16 could contribute to recruitment of malignant T cells in MF. We found elevated TSLP and IL-16 in very early stage patients ’ plasma and skin biopsies, prior to elevation in CCL22. Both TSLP and IL-16 induced

  • regulation of cellular processes by Interleukin 16 in homeostasis and cancer
    Journal of Cellular Physiology, 2014
    Co-Authors: Jillian M Richmond, Marina Tuzova, William W Cruikshank
    Abstract:

    Interleukin-16 (IL-16) is generated as a precursor molecule that is cleaved by caspase-3 to produce a pro-IL-16 molecule that functions as a regulator of T cell growth, and a secreted peptide that functions as a CD4 and/or CD9 ligand for induction of cell motility and activation. IL-16 has been predominantly studied as a contributing factor in the orchestration of an immune response; however, more recently IL-16 bioactivity has been closely associated with the progression of a number of different cancers. While the association between IL-16 plasma levels and tumor progression has been reported for many types of cancer, the mechanism for IL-16 involvement has been partially elucidated for three of the cancer types, cutaneous T cell lymphoma (CTCL), multiple myeloma (MM), and breast cancer. The mechanism for promoting cell growth is different in each of these cancers and involves a sequence mutation in the pro-molecule facilitating decreased p27KIP1 levels in CTCL; over expression of the secreted IL-16 molecule to induce proliferation in CTCL T cells, and plasma cells in MM; and increased secreted IL-16 acting to recruit CD4+ pro-tumor macrophages in breast cancer. This article will review the cellular process for generating IL-16, the biological activities for both the pro- and secreted forms of the protein, and then the mechanism by which these forms contribute to cancer progression. As a soluble cytokine the ability to reduce or eliminate IL-16 synthesis through siRNA approaches or bioactivity through the use of neutralizing antibody treatment may represent a novel therapeutic approach. J. Cell. Physiol. 229: 139–147, 2014. © 2013 Wiley Periodicals, Inc.

  • a homologous form of human Interleukin 16 is implicated in microglia recruitment following nervous system injury in leech hirudo medicinalis
    Glia, 2010
    Co-Authors: Francoise Croq, Marina Tuzova, William W Cruikshank, Jacopo Vizioli, Muriel Tahtouh, Pierreeric Sautiere, Christelle Van Camp, Michel Salzet, Joel Pestel, Christophe Lefebvre
    Abstract:

    In contrast to mammals, the medicinal leech Hirudo medicinalis can completely repair its central nervous system (CNS) after injury. This invertebrate model offers unique opportunities to study the molecular and cellular basis of the CNS repair processes. When the leech CNS is injured, microglial cells migrate and accumulate at the site of lesion, a phenomenon known to be essential for the usual sprouting of injured axons. In the present study, we demonstrate that a new molecule, designated HmIL-16, having functional homologies with human Interleukin-16 (IL-16), has chemotactic activity on leech microglial cells as observed using a gradient of human IL-16. Preincubation of microglial cells either with an anti-human IL-16 antibody or with anti-HmIL-16 antibody significantly reduced microglia migration induced by leech-conditioned medium. Functional homology was demonstrated further by the ability of HmIL-16 to promote human CD41 T cell migration which was inhibited by antibody against human IL-16, an IL-16 antagonist peptide or soluble CD4. Immunohistochemistry of leech CNS indicates that HmIL-16 protein present in the neurons is rapidly transported and stored along the axonal processes to promote the recruitment of microglial cells to the injured axons. To our knowledge, this is the first identification of a functional Interleukin-16 homologue in invertebrate CNS. The ability of HmIL-16 to recruit microglial cells to sites of CNS injury suggests a role for HmIL-16 in the crosstalk between neurons and microglia in the leech CNS repair. V C 2010 Wiley-Liss, Inc.

  • neutralization of Interleukin 16 protects nonobese diabetic mice from autoimmune type 1 diabetes by a ccl4 dependent mechanism
    Diabetes, 2010
    Co-Authors: Craig Meagher, William W Cruikshank, Josh Beilke, G A Arreaza, Wei Chen, Konstantin V Salojin, Noah Horst, Terry L Delovitch
    Abstract:

    Abstract Objective– The progressive infiltration of pancreatic islets by lymphocytes is mandatory for development of autoimmune type 1 diabetes (T1D). This inflammatory process is mediated by several mediators that are potential therapeutic targets to arrest development of T1D. In this study, we investigate the role of one of these mediators, Interleukin-16 (IL-16), in the pathogenesis of T1D in nonobese diabetic (NOD) mice. Research design and methods– At various stages of progression of T1D, we characterized IL-16 in islets using GEArray™ technology and immunoblot analysis and also quantitated IL-16 activity in cell migration assays. IL-16 expression was localized in islets by immunofluorescence and confocal imaging. In vivo neutralization studies were performed to assess the role of IL-16 in the pathogenesis of T1D. Results– The increased expression of IL-16 in islets correlated with the development of invasive insulitis. IL-16 immunoreactivity was found in islet infiltrating T cells, B cells, NK cells, and dendritic cells (DC), and within an insulitic lesion IL-16 was derived from infiltrating cells. CD4 + and CD8 + T cells as well as B220 + B cells were identified as sources of secreted IL-16. Blockade of IL-16 in vivo protected against T1D by interfering with recruitment of CD4 + T cells to the pancreas, and this protection required the activity of the chemokine CCL4. Conclusions– IL-16 production by leukocytes in islets augments the severity of insulitis during the onset of T1D. IL-16 and CCL4 appear to function as counter-regulatory proteins during disease development. Neutralization of IL-16 may represent a novel therapy for the prevention of T1D.

  • transforming growth factor β1 and laminin 111 cooperate in the induction of Interleukin 16 expression in synovial fibroblasts from patients with rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2010
    Co-Authors: Katrin Warstat, William W Cruikshank, Maik Hoberg, Maximilian Rudert, Shanli Tsui, Thomas Pap, Brigitte Angres, Mike Essl, Terry J Smith, Gerd Klein
    Abstract:

    Objectives: In synovial tissues of patients with rheumatoid arthritis (RA), strong expression of laminins and integrins co-localises with increased expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through increased expression of cytokines and chemoattractant factors, one of which is Interleukin-16 (IL16). A study was undertaken to investigate the regulatory pathways of IL16 in SF from patients with RA (RA-SF) and osteoarthritis (OA-SF). Methods: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. The expression of IL16 was investigated by quantitative RT-PCR, immunoblotting and ELISA; its biological activity was determined by a cell migration assay. Cell–matrix interactions were investigated by cell binding and attachment assays. Relevant intracellular signalling pathways were studied by immunoblotting and with pharmacological blocking reagents. Results: Stimulation of SF with transforming growth factor β 1 (TGF-β 1 ) and growth on laminin-111 (LM-111) significantly increased the expression of IL16. Binding to LM-111 induced significantly more IL16 mRNA in RA-SF than in OA-SF (p 1 -activated and in LM-111+TGF-β 1 -activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL16 regulation involved p38MAPK, ERK1/2 and SMAD2 signalling, but not NFκB. Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β 1 triggers a significant IL16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL16 induction represents a novel pathway leading to IL16 production in RA-SF but not in OA-SF, which operates independently of NFκB signalling.

Hardy Kornfeld - One of the best experts on this subject based on the ideXlab platform.

  • Interleukin 16 inhibits Interleukin 13 production by allergen stimulated blood mononuclear cells
    Immunology, 2006
    Co-Authors: Souad El Bassam, Hardy Kornfeld, Stephane Pinsonneault, Fucheng Ren, Jose Menezes, Sophie Laberge
    Abstract:

    Expression of Interleukin (IL)-16 is increased in bronchial mucosal biopsies of atopic asthmatics compared to normal controls. The functional significance of increased expression of IL-16 at sites of allergic inflammation is not yet clear. We have previously shown that IL-16 inhibits IL-5 secretion by allergen-stimulated peripheral blood mononuclear cells (PBMC). We investigated whether IL-16 inhibits the production of other T helper 2 cytokines, namely IL-13 and IL-4, by allergen-specific T cells. PBMC from ragweed-sensitive atopic subjects were stimulated with allergen extract for cytokine production in the presence or absence of rhIL-16. Production of cytokines was assessed by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. To evaluate whether the modulatory effect of IL-16 on cytokine synthesis was mediated by interferon-gamma (IFN-gamma), IL-10, IL-12 or IL-18, allergen-stimulated PBMC were cultured in presence of IL-16 and neutralizing concentrations of relevant antibodies. Allergen-stimulated PBMC produced significantly elevated levels of IL-13 (90-740 pg/ml) as compared to unstimulated PBMC (0-375 pg/ml, P < 0.01). Addition of rhIL-16 resulted in down-regulation of IL-13 mRNA expression as well as significantly reduced amounts of IL-13 released by allergen-stimulated PBMC (0-457 pg/ml, P < 0.001), as observed for IL-5. No effect of IL-16 was observed on IL-4 mRNA expression. Treatment with IL-16 resulted in increased levels of IL-10 and IL-18 in allergen-stimulated cell culture. Neutralization of IFN-gamma, IL-12, IL-10 or IL-18 did not alter the inhibitory effects of IL-16 on IL-13 and IL-5 secretion by allergen-stimulated PBMC. IL-16 did not modify IL-13 synthesis by anti-CD3-stimulated CD4(+) T cells, but it significantly reduced the production of IL-5. These data suggest that IL-16 may play an important immunoregulatory role in allergic states in response to allergen.

  • cd8 t lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting cd4 mononuclear cells through the expression of Interleukin 16
    Circulation, 2005
    Co-Authors: Eugenio Stabile, Tim Kinnaird, Andrea La Sala, Sue Kim Hanson, Craig Watkins, Umberto Campia, Matie Shou, Stephan Zbinden, Shmuel Fuchs, Hardy Kornfeld
    Abstract:

    Background— Previous studies have demonstrated that macrophages and CD4+ T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8+ T cells also play a role. Thus, after acute cerebral ischemia, CD8+ T cells infiltrate the perivascular space and secrete Interleukin-16 (IL-16), a potent chemoattractant for monocytes and CD4+ T cells. We tested whether CD8+ T lymphocytes contribute to collateral vessel development and whether the lack of circulating CD8+ T cells prevents IL-16 expression, impairs CD4+ mononuclear cell recruitment, and reduces collateral vessel growth after femoral artery ligation in CD8−/− mice. Methods and Results— After surgical excision of the femoral artery, laser Doppler perfusion imaging demonstrated reduced blood flow recovery in CD8−/− mice compared with C57/BL6 mice (ischemic/nonischemic limb at day 28, 0.66±0.04 versus 0.87±0.04, respectively; P<0.01). This resulted in greater calf muscle atrophy (mean fiber area, 785±68 versus 1067±69 μm2, re...

  • nuclear translocation of the n terminal prodomain of Interleukin 16
    Journal of Biological Chemistry, 2001
    Co-Authors: Yujun Zhang, Hardy Kornfeld, William W Cruikshank, Sue Kim, Christine C Reardon
    Abstract:

    Abstract Interleukin-16 (IL-16) is a pleiotropic cytokine that functions as a chemoattractant factor, a modulator of T cell activation, and an inhibitor of human immunodeficiency virus (HIV) replication. These diverse functions are exclusively attributed to the secreted C-terminal peptide of 121 amino acids (mature IL-16), which is cleaved from the precursor protein (pro-IL-16) by caspase-3. Human pro-IL-16 is comprised of 631 amino acids with three PDZ domains, one of which is present in secreted mature IL-16. No cellular localization or biologic functions have been ascribed to the unusually large and highly conserved N-terminal prodomain formed as a result of proteolytic release of the third PDZ domain of pro-IL-16. Here we show that the N-terminal prodomain of pro-IL-16 translocates into the nucleus following cleavage of the C-terminal segment. The nuclear localization signal of pro-IL-16 consists of a classical bipartite nuclear targeting motif. We also show that the nuclear targeting of the IL-16 prodomain induces a G0/G1 arrest in the cell cycle. Taken together, the high degree of conservation of the prodomain among species, the presence of two PDZ motifs, and the nuclear localization and subsequent inhibitory effect on cell cycle progression suggest that pro-IL-16 is cleaved into two functional proteins, a C-terminal-secreted cytokine and an N-terminal product, which affects the cell cycle.

  • Interleukin 16 implications for cd4 functions and hiv 1 progression
    Immunology Today, 2000
    Co-Authors: Hardy Kornfeld, Thomas C Ryan, William W Cruikshank
    Abstract:

    In this article, David Center and colleagues clarify the controversies that have emerged over the unique structure of Interleukin 16 and its anti-HIV-1 activity. Interleukin 16 is a ligand for CD4, and this implies CD4 acts as a sentinel receptor that can switch CD4+ T cells between immune and inflammatory functions.

  • identification of a cd4 domain required for Interleukin 16 binding and lymphocyte activation
    Journal of Biological Chemistry, 1999
    Co-Authors: Yu Liu, William W Cruikshank, Terence Oloughlin, Phillip Oreilly, Hardy Kornfeld
    Abstract:

    Abstract Interleukin-16 (IL-16) activates CD4+ cells, possibly by direct interaction with CD4. IL-16 structure and function are highly conserved across species, suggesting similar conservation of a putative IL-16 binding site on CD4. Comparison of the human CD4 amino acid sequence with that of several different species revealed that immunoglobulin-like domain 4 is the most conserved extracellular region. Potential interaction of this domain with IL-16 was studied by testing murine D4 sequence-based oligopeptides for inhibition of IL-16 chemoattractant activity and inhibition of IL-16 binding to CD4 in vitro. Three contiguous 12-residue D4 region peptides (designated A, B, and C) blocked IL-16 chemoattractant activity, with peptide B the most potent. Peptides A and B were synergistic for inhibition, but peptide C was not. Peptides A and B also blocked IL-16 binding to CD4 in vitro, whereas peptide C did not. CD4, in addition to its known function as a receptor for major histocompatibility complex class II, contains a binding site for IL-16 in the D4 domain. The D4 residues required for IL-16 binding overlap those previously shown to participate in CD4-CD4 dimerization following class II major histocompatibility complex binding, providing a mechanistic explanation for the known function of IL-16 to inhibit the mixed lymphocyte reaction.

Animesh Barua - One of the best experts on this subject based on the ideXlab platform.

  • abstract as14 contrast enhanced Interleukin 16 targeted imaging detects ovarian tumor at early stage
    Clinical Cancer Research, 2015
    Co-Authors: Animesh Barua, Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu
    Abstract:

    Background: The high rate of death of ovarian cancer (OVCA) patients can be reduced if it is detected at early stage. Neither suggested serum markers nor the currently available traditional transvaginal ultrasound (TVUS) imaging or their combinations can detect OVCA at early stage. No imaging target in the ovary for TVUS imaging corresponding to the suggested serum markers has been defined. Moreover, due to the limited resolution, TVUS imaging cannot detect OVCA at early stage. Thus, new imaging target(s) together with improvement in resolution is necessary for early OVCA detection by TVUS imaging. Interleukin 16 (IL-16), a proinflammatory cytokine, associated with longstanding unresolved inflammation due to frequent ovulation, has been reported to be increased during OVCA development. IL-16 is expressed by the ovarian malignant cells and tumor associated neoangiogenic (TAN) microvessels. Thus IL-16 represents a potential marker of early OVCA which can be detected in vivo by TVUS imaging provided a molecular targeted contrast enhanced imaging agent can be developed. Objective: The goal of this study was to develop and test the efficacy of molecular (IL-16)-targeted ultrasound imaging probe for the detection of early OVCA. Materials and Methods: 3-years old (n=150) White Leghorn laying hens with normal or low egg laying rates or stopped-egg laying were scanned by TVUS before and after intravenous injection with IL-16-targeted microbubbles. IL-16-targeted imaging agents were prepared by conjugating anti-chicken IL-16 antibodies with Targetster® containing microbubbles (Targeson Inc, San Diego). All images were archived and analyzed offline. Serum samples were collected, hens were euthanized, ovarian tissues were processed for paraffin or frozen sections and nuclear matrix protein (NMP) extraction. Ovarian tumors were confirmed by gross morphology and routine histology. Sera were tested for anti-NMP antibodies (a marker of malignant nuclear transformation) and IL-16 levels by immunoassay and 1- & 2D-Western blot (WB). The frequencies of IL-16 expressing cells were determined by immunohistochemistry (IHC). Results: IL-16-targeted microbubbles bounded with ovarian tumors and appeared as shining mass of irregular-shape. Compared with non-targeted, IL-16-targeted imaging increased the visualization of ovarian tumors remarkably. All hens with suspected tumor mass (n=23, 7 early and 16 late stages) were detected by IL-16-targeted imaging and confirmed by gross examination. The frequency of IL-16 expressing cells detected by IHC confirmed the prediction of targeted ultrasound imaging. Serum levels of IL-16 were higher in OVCA hens than in normal hens and correlated with the frequencies of IL-16 expressing cells and ovarian TAN vessels. Prevalence of anti-NMP antibodies were not detected in normal hens while all hens with OVCA were positive. Immunoreactive tumor antigens (NMPs) of 50-80kDa were detected by 2D-WB. Conclusion: IL-16-targeted ultrasound imaging enhanced the visualization of ovarian tumors remarkably. The enhanced intensity of IL-16-targeted imaging was correlated with serum IL-16 levels and the prevalence of anti-NMP antibodies. Thus, IL-16-targeted imaging in association with serum anti-NMP antibodies may improve OVCA detection at early stage. These results will form a foundation for a clinical study. Support: Dept. of Defense award # W81XWH-12-1-0460. Citation Format: Animesh Barua, Aparna Yellapa, Pincas Bitterman, Janice M Bahr, Sanjib Basu, Sameer Sharma, Jacques S. Abramowicz. Contrast enhanced Interleukin 16 targeted imaging detects ovarian tumor at early stage [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS14.

  • Interleukin 16 il 16 targeted ultrasound imaging agent improves detection of ovarian tumors in laying hens a preclinical model of spontaneous ovarian cancer
    BioMed Research International, 2015
    Co-Authors: Animesh Barua, Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu, Malavika K Adur, Chet W Utterback
    Abstract:

    Limited resolution of transvaginal ultrasound (TVUS) scanning is a significant barrier to early detection of ovarian cancer (OVCA). Contrast agents have been suggested to improve the resolution of TVUS scanning. Emerging evidence suggests that expression of Interleukin 16 (IL-16) by the tumor epithelium and microvessels increases in association with OVCA development and offers a potential target for early OVCA detection. The goal of this study was to examine the feasibility of IL-16-targeted contrast agents in enhancing the intensity of ultrasound imaging from ovarian tumors in hens, a model of spontaneous OVCA. Contrast agents were developed by conjugating biotinylated anti-IL-16 antibodies with streptavidin coated microbubbles. Enhancement of ultrasound signal intensity was determined before and after injection of contrast agents. Following scanning, ovarian tissues were processed for the detection of IL-16 expressing cells and microvessels. Compared with precontrast, contrast imaging enhanced ultrasound signal intensity significantly in OVCA hens at early (P < 0.05) and late stages (P < 0.001). Higher intensities of ultrasound signals in OVCA hens were associated with increased frequencies of IL-16 expressing cells and microvessels. These results suggest that IL-16-targeted contrast agents improve the visualization of ovarian tumors. The laying hen may be a suitable model to test new imaging agents and develop targeted anti-OVCA therapeutics.

  • Interleukin 16 expression changes in association with ovarian malignant transformation
    American Journal of Obstetrics and Gynecology, 2014
    Co-Authors: Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu, Alfred Guirguis, Animesh Barua
    Abstract:

    Objective Long-term unresolved inflammation has been suggested as a risk factor for the development of various malignancies. The goal of this study was to examine whether the expression of Interleukin (IL)-16, a proinflammatory cytokine, changes in association with ovarian cancer (OVCA) development. Study Design In an exploratory study, changes in IL-16 expression in association with OVCA development and progression were determined using ovarian tissues and serum samples from healthy subjects (n = 10) and patients with benign (n = 10) and malignant ovarian tumors at early (n = 8) and late (n = 20) stages. In the prospective study, laying hens, a preclinical model of spontaneous OVCA, were monitored (n = 200) for 45 weeks with serum samples collected at 15-week interval. Changes in serum levels of IL-16 relative to OVCA development were examined. Results The frequency of IL-16–expressing cells increased significantly in patients with OVCA ( P P P P P Conclusion This study showed that tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression.

  • abstract a64 association of Interleukin 16 with early metastasis of ovarian tumors
    Clinical Cancer Research, 2013
    Co-Authors: Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu, Animesh Barua
    Abstract:

    Introduction: Ovarian cancer (OVCA) differs from other malignancies in its specific dissemination pattern that the tumor typically spreads in a diffuse intra-abdominal fashion rather than systemic circulation. Interactions among different cell types and their secretory products in the tumor microenvironment may contribute to the tumor development and metastasis. Interleukin 16 (IL-16) is a chemoattractant and pro-angiogenic cytokine involved in multiple immunopathobiological processes. IL-16 is expressed by several cell types including CD8 T cells and macrophages and occasionally by malignant cells. IL-16 expression is reported to be increased in several tumors including OVCA. Thus, IL-16 may be involved in the development and metastasis of ovarian tumors, if so, how IL-16 enhances tumor metastasis is not known. CD9, a member of tetraspanin family, has been implicated in the regulation of cell proliferation, invasion and motility. Emerging studies reported CD9 as a receptor for IL-16. Objectives: The goal of this study was to determine (1) whether IL-16 is associated with ovarian tumor metastasis in the vicinity of tumors including the omentum and (2) if so, to determine how IL-16 is associated with ovarian tumor metastasis. In this study we examined association of IL-16 and its receptor (CD9) expression with respect to ovarian tumor development and progression. The association of CD8+T cells and IL-16 expression during tumor initiation was examined in laying hens, an animal model of spontaneous OVCA. Methods: Experiment-1: Tumor specimen from patients with serous OVCA (10 early and 20 late stages), serous benign ovarian tumors (n=10) and normal (n=5, from patients underwent hysterectomies for non-ovarian disease) and omental tissues (n= 5, each of OVCA and benign) were used. Changes in IL-6 and CD9 expression in tumor tissues (ovaries and omentum) were examined by immunohistochemistry, proteomics and by quantitative polymerase chain reaction (qPCR). Experiment-II: Laying hens with normal ovaries (n=10) or microscopic OVCA (n=10) were examined for CD8 T cells and IL-16 expressing cells as mentioned above. The correlation between the IL-16 and CD8+ T cells were examined. In addition, to examine the effects of IL-16 on CD9 expression, normal ovarian surface epithelial (OSE) cells were treated with recombinant IL-16 protein. Results: Compared with normal ovaries and benign tumors, the frequencies of IL-16 expressing cells were significantly high in early stage OVCA ( P P Conclusions: The results of the present study suggest that increased IL-16 expression may be associated with enhanced CD9 expression which may be a factor for ovarian tumor progression and metastasis to the omental tissues. Increased CD8+ T cells in the tumor vicinity suggests that CD8+ T cells may be a source of enhanced IL-16 expression in developing ovarian tumors. Support: DOD award # W81XWH-11-1-0510 Citation Format: Aparna Yellapa, Pincas Bitterman, Jacques S. Abramowicz, Janice M. Bahr, Sameer Sharma, Sanjib Basu, Animesh Barua. Association of Interleukin 16 with early metastasis of ovarian tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A64.

  • association of Interleukin 16 with the development of ovarian tumor and tumor associated neoangiogenesis in laying hen model of spontaneous ovarian cancer
    International Journal of Gynecological Cancer, 2012
    Co-Authors: Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sanjib Basu, Seby L Edassery, Krishna Penumatsa, Jacob Rotmensch, Animesh Barua
    Abstract:

    Objective Tumor-associated neoangiogenesis (TAN) is an early event in ovarian tumor development. Interleukin 16 (IL-16) is a proangiogenic cytokine that stimulates production of neoangiogenic factors. The goal of this study was to determine the association of IL-16 with tumor development and ovarian TAN in laying hens, an animal model of spontaneous ovarian cancer (OVCA). Methods Sera and ovarian tissues from 3-year-old laying hens were collected and processed for histopathologic, immunoassay, immunohistochemistry, immunoblotting, and molecular biological studies to determine the tissue expression and serum levels of IL-16. Samples were divided into 3 groups based on the diagnosis of the histopathologic ovarian tissue examination, namely, normal (healthy control, n = 81), early (n = 23 including 11 with microscopic OVCA), and late stages (n = 16) of OVCA. Results Serum levels of IL-16 were significantly higher in hens with microscopic, early, and late stages of OVCA than normal hens (P Conclusions The results of the study suggest that changes in serum levels of IL-16 are associated with tumor development and TAN. Thus, serum IL-16 levels may be an indicator of ovarian TAN at the early stage of OVCA.

Jacques S Abramowicz - One of the best experts on this subject based on the ideXlab platform.

  • abstract as14 contrast enhanced Interleukin 16 targeted imaging detects ovarian tumor at early stage
    Clinical Cancer Research, 2015
    Co-Authors: Animesh Barua, Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu
    Abstract:

    Background: The high rate of death of ovarian cancer (OVCA) patients can be reduced if it is detected at early stage. Neither suggested serum markers nor the currently available traditional transvaginal ultrasound (TVUS) imaging or their combinations can detect OVCA at early stage. No imaging target in the ovary for TVUS imaging corresponding to the suggested serum markers has been defined. Moreover, due to the limited resolution, TVUS imaging cannot detect OVCA at early stage. Thus, new imaging target(s) together with improvement in resolution is necessary for early OVCA detection by TVUS imaging. Interleukin 16 (IL-16), a proinflammatory cytokine, associated with longstanding unresolved inflammation due to frequent ovulation, has been reported to be increased during OVCA development. IL-16 is expressed by the ovarian malignant cells and tumor associated neoangiogenic (TAN) microvessels. Thus IL-16 represents a potential marker of early OVCA which can be detected in vivo by TVUS imaging provided a molecular targeted contrast enhanced imaging agent can be developed. Objective: The goal of this study was to develop and test the efficacy of molecular (IL-16)-targeted ultrasound imaging probe for the detection of early OVCA. Materials and Methods: 3-years old (n=150) White Leghorn laying hens with normal or low egg laying rates or stopped-egg laying were scanned by TVUS before and after intravenous injection with IL-16-targeted microbubbles. IL-16-targeted imaging agents were prepared by conjugating anti-chicken IL-16 antibodies with Targetster® containing microbubbles (Targeson Inc, San Diego). All images were archived and analyzed offline. Serum samples were collected, hens were euthanized, ovarian tissues were processed for paraffin or frozen sections and nuclear matrix protein (NMP) extraction. Ovarian tumors were confirmed by gross morphology and routine histology. Sera were tested for anti-NMP antibodies (a marker of malignant nuclear transformation) and IL-16 levels by immunoassay and 1- & 2D-Western blot (WB). The frequencies of IL-16 expressing cells were determined by immunohistochemistry (IHC). Results: IL-16-targeted microbubbles bounded with ovarian tumors and appeared as shining mass of irregular-shape. Compared with non-targeted, IL-16-targeted imaging increased the visualization of ovarian tumors remarkably. All hens with suspected tumor mass (n=23, 7 early and 16 late stages) were detected by IL-16-targeted imaging and confirmed by gross examination. The frequency of IL-16 expressing cells detected by IHC confirmed the prediction of targeted ultrasound imaging. Serum levels of IL-16 were higher in OVCA hens than in normal hens and correlated with the frequencies of IL-16 expressing cells and ovarian TAN vessels. Prevalence of anti-NMP antibodies were not detected in normal hens while all hens with OVCA were positive. Immunoreactive tumor antigens (NMPs) of 50-80kDa were detected by 2D-WB. Conclusion: IL-16-targeted ultrasound imaging enhanced the visualization of ovarian tumors remarkably. The enhanced intensity of IL-16-targeted imaging was correlated with serum IL-16 levels and the prevalence of anti-NMP antibodies. Thus, IL-16-targeted imaging in association with serum anti-NMP antibodies may improve OVCA detection at early stage. These results will form a foundation for a clinical study. Support: Dept. of Defense award # W81XWH-12-1-0460. Citation Format: Animesh Barua, Aparna Yellapa, Pincas Bitterman, Janice M Bahr, Sanjib Basu, Sameer Sharma, Jacques S. Abramowicz. Contrast enhanced Interleukin 16 targeted imaging detects ovarian tumor at early stage [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS14.

  • Interleukin 16 il 16 targeted ultrasound imaging agent improves detection of ovarian tumors in laying hens a preclinical model of spontaneous ovarian cancer
    BioMed Research International, 2015
    Co-Authors: Animesh Barua, Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu, Malavika K Adur, Chet W Utterback
    Abstract:

    Limited resolution of transvaginal ultrasound (TVUS) scanning is a significant barrier to early detection of ovarian cancer (OVCA). Contrast agents have been suggested to improve the resolution of TVUS scanning. Emerging evidence suggests that expression of Interleukin 16 (IL-16) by the tumor epithelium and microvessels increases in association with OVCA development and offers a potential target for early OVCA detection. The goal of this study was to examine the feasibility of IL-16-targeted contrast agents in enhancing the intensity of ultrasound imaging from ovarian tumors in hens, a model of spontaneous OVCA. Contrast agents were developed by conjugating biotinylated anti-IL-16 antibodies with streptavidin coated microbubbles. Enhancement of ultrasound signal intensity was determined before and after injection of contrast agents. Following scanning, ovarian tissues were processed for the detection of IL-16 expressing cells and microvessels. Compared with precontrast, contrast imaging enhanced ultrasound signal intensity significantly in OVCA hens at early (P < 0.05) and late stages (P < 0.001). Higher intensities of ultrasound signals in OVCA hens were associated with increased frequencies of IL-16 expressing cells and microvessels. These results suggest that IL-16-targeted contrast agents improve the visualization of ovarian tumors. The laying hen may be a suitable model to test new imaging agents and develop targeted anti-OVCA therapeutics.

  • Interleukin 16 expression changes in association with ovarian malignant transformation
    American Journal of Obstetrics and Gynecology, 2014
    Co-Authors: Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu, Alfred Guirguis, Animesh Barua
    Abstract:

    Objective Long-term unresolved inflammation has been suggested as a risk factor for the development of various malignancies. The goal of this study was to examine whether the expression of Interleukin (IL)-16, a proinflammatory cytokine, changes in association with ovarian cancer (OVCA) development. Study Design In an exploratory study, changes in IL-16 expression in association with OVCA development and progression were determined using ovarian tissues and serum samples from healthy subjects (n = 10) and patients with benign (n = 10) and malignant ovarian tumors at early (n = 8) and late (n = 20) stages. In the prospective study, laying hens, a preclinical model of spontaneous OVCA, were monitored (n = 200) for 45 weeks with serum samples collected at 15-week interval. Changes in serum levels of IL-16 relative to OVCA development were examined. Results The frequency of IL-16–expressing cells increased significantly in patients with OVCA ( P P P P P Conclusion This study showed that tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression.

  • abstract a64 association of Interleukin 16 with early metastasis of ovarian tumors
    Clinical Cancer Research, 2013
    Co-Authors: Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sameer Sharma, Sanjib Basu, Animesh Barua
    Abstract:

    Introduction: Ovarian cancer (OVCA) differs from other malignancies in its specific dissemination pattern that the tumor typically spreads in a diffuse intra-abdominal fashion rather than systemic circulation. Interactions among different cell types and their secretory products in the tumor microenvironment may contribute to the tumor development and metastasis. Interleukin 16 (IL-16) is a chemoattractant and pro-angiogenic cytokine involved in multiple immunopathobiological processes. IL-16 is expressed by several cell types including CD8 T cells and macrophages and occasionally by malignant cells. IL-16 expression is reported to be increased in several tumors including OVCA. Thus, IL-16 may be involved in the development and metastasis of ovarian tumors, if so, how IL-16 enhances tumor metastasis is not known. CD9, a member of tetraspanin family, has been implicated in the regulation of cell proliferation, invasion and motility. Emerging studies reported CD9 as a receptor for IL-16. Objectives: The goal of this study was to determine (1) whether IL-16 is associated with ovarian tumor metastasis in the vicinity of tumors including the omentum and (2) if so, to determine how IL-16 is associated with ovarian tumor metastasis. In this study we examined association of IL-16 and its receptor (CD9) expression with respect to ovarian tumor development and progression. The association of CD8+T cells and IL-16 expression during tumor initiation was examined in laying hens, an animal model of spontaneous OVCA. Methods: Experiment-1: Tumor specimen from patients with serous OVCA (10 early and 20 late stages), serous benign ovarian tumors (n=10) and normal (n=5, from patients underwent hysterectomies for non-ovarian disease) and omental tissues (n= 5, each of OVCA and benign) were used. Changes in IL-6 and CD9 expression in tumor tissues (ovaries and omentum) were examined by immunohistochemistry, proteomics and by quantitative polymerase chain reaction (qPCR). Experiment-II: Laying hens with normal ovaries (n=10) or microscopic OVCA (n=10) were examined for CD8 T cells and IL-16 expressing cells as mentioned above. The correlation between the IL-16 and CD8+ T cells were examined. In addition, to examine the effects of IL-16 on CD9 expression, normal ovarian surface epithelial (OSE) cells were treated with recombinant IL-16 protein. Results: Compared with normal ovaries and benign tumors, the frequencies of IL-16 expressing cells were significantly high in early stage OVCA ( P P Conclusions: The results of the present study suggest that increased IL-16 expression may be associated with enhanced CD9 expression which may be a factor for ovarian tumor progression and metastasis to the omental tissues. Increased CD8+ T cells in the tumor vicinity suggests that CD8+ T cells may be a source of enhanced IL-16 expression in developing ovarian tumors. Support: DOD award # W81XWH-11-1-0510 Citation Format: Aparna Yellapa, Pincas Bitterman, Jacques S. Abramowicz, Janice M. Bahr, Sameer Sharma, Sanjib Basu, Animesh Barua. Association of Interleukin 16 with early metastasis of ovarian tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A64.

  • association of Interleukin 16 with the development of ovarian tumor and tumor associated neoangiogenesis in laying hen model of spontaneous ovarian cancer
    International Journal of Gynecological Cancer, 2012
    Co-Authors: Aparna Yellapa, Pincas Bitterman, Jacques S Abramowicz, Janice M Bahr, Sanjib Basu, Seby L Edassery, Krishna Penumatsa, Jacob Rotmensch, Animesh Barua
    Abstract:

    Objective Tumor-associated neoangiogenesis (TAN) is an early event in ovarian tumor development. Interleukin 16 (IL-16) is a proangiogenic cytokine that stimulates production of neoangiogenic factors. The goal of this study was to determine the association of IL-16 with tumor development and ovarian TAN in laying hens, an animal model of spontaneous ovarian cancer (OVCA). Methods Sera and ovarian tissues from 3-year-old laying hens were collected and processed for histopathologic, immunoassay, immunohistochemistry, immunoblotting, and molecular biological studies to determine the tissue expression and serum levels of IL-16. Samples were divided into 3 groups based on the diagnosis of the histopathologic ovarian tissue examination, namely, normal (healthy control, n = 81), early (n = 23 including 11 with microscopic OVCA), and late stages (n = 16) of OVCA. Results Serum levels of IL-16 were significantly higher in hens with microscopic, early, and late stages of OVCA than normal hens (P Conclusions The results of the study suggest that changes in serum levels of IL-16 are associated with tumor development and TAN. Thus, serum IL-16 levels may be an indicator of ovarian TAN at the early stage of OVCA.

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  • transforming growth factor β1 and laminin 111 cooperate in the induction of Interleukin 16 expression in synovial fibroblasts from patients with rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2010
    Co-Authors: Katrin Warstat, William W Cruikshank, Maik Hoberg, Maximilian Rudert, Shanli Tsui, Thomas Pap, Brigitte Angres, Mike Essl, Terry J Smith, Gerd Klein
    Abstract:

    Objectives: In synovial tissues of patients with rheumatoid arthritis (RA), strong expression of laminins and integrins co-localises with increased expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through increased expression of cytokines and chemoattractant factors, one of which is Interleukin-16 (IL16). A study was undertaken to investigate the regulatory pathways of IL16 in SF from patients with RA (RA-SF) and osteoarthritis (OA-SF). Methods: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. The expression of IL16 was investigated by quantitative RT-PCR, immunoblotting and ELISA; its biological activity was determined by a cell migration assay. Cell–matrix interactions were investigated by cell binding and attachment assays. Relevant intracellular signalling pathways were studied by immunoblotting and with pharmacological blocking reagents. Results: Stimulation of SF with transforming growth factor β 1 (TGF-β 1 ) and growth on laminin-111 (LM-111) significantly increased the expression of IL16. Binding to LM-111 induced significantly more IL16 mRNA in RA-SF than in OA-SF (p 1 -activated and in LM-111+TGF-β 1 -activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL16 regulation involved p38MAPK, ERK1/2 and SMAD2 signalling, but not NFκB. Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β 1 triggers a significant IL16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL16 induction represents a novel pathway leading to IL16 production in RA-SF but not in OA-SF, which operates independently of NFκB signalling.

  • immunoglobulin g from patients with graves disease induces Interleukin 16 and rantes expression in cultured human thyrocytes a putative mechanism for t cell infiltration of the thyroid in autoimmune disease
    Endocrinology, 2006
    Co-Authors: Andrew G Gianoukakis, William W Cruikshank, Terry J Smith, Raymond S Douglas, Chris S King
    Abstract:

    Mechanisms underlying lymphocyte infiltration of the thyroid gland and orbit in Graves’ disease (GD) are poorly understood. The IGF-I receptor (IGF-IR) is a newly recognized self-antigen that, when activated in GD fibroblasts by IGF-I or GD-IgGs, provokes the expression of IL-16 and RANTES (regulated upon activation, normal T cell expressed and secreted)-dependent T lymphocyte chemoattraction and hyaluronan synthesis. IL-16 is a CD4+-specific ligand, and RANTES is a C-C chemokine. Here we report that IGF-I and GD-IgG could induce IL-16 and RANTES in cultured human thyrocytes in a time-dependent manner. Importantly, human TSH failed to induce either chemoattractant. This induction could be attenuated by dexamethasone. Rapamycin, a specific inhibitor of the FRAP/mammalian target of rapamycin/p70s6k pathway, prevented GD-IgG-provoked IL-16 synthesis. IH7, a monoclonal antibody directed at IGF-IR also blocked the induction of chemoattraction as well as RANTES mRNA synthesis. Our findings suggest that thyrocyt...

  • cytokine induced lymphocyte chemoattraction from cultured human thyrocytes evidence for Interleukin 16 and regulated upon activation normal t cell expressed and secreted expression
    Endocrinology, 2003
    Co-Authors: William W Cruikshank, Noah Horst, Terry J Smith, Andrew G Gianoukakis, Leon J Martino
    Abstract:

    Mediators of lymphocyte infiltration in inflammatory thyroid disease have yet to be identified. Here we examine the ability of IL-1 to enhance the production of chemoattractants by human thyrocytes. Primary cultures, when treated with the cytokine, release T lymphocyte chemotactic activity. The effect of IL-1 is time dependent, and the chemoattraction activity can be partially attenuated by the addition of either anti-IL-16 or anti-regulated upon activation, normal T cell expressed, and secreted (RANTES) neutralizing antibodies. IL-16 is a CD4-specific ligand, and RANTES is a C-C type chemokine that targets monocytes and lymphocytes. These chemoattractants could be detected by specific ELISAs in conditioned medium from IL-1 treated thyrocytes. Northern analysis revealed that thyrocytes express high constitutive levels of IL-16 mRNA, which were invariant with regard to IL-1 (10 ng/ml) or glucocorticoid treatment. RANTES mRNA was not detected in control cultures but was strongly induced by the cytokine. IL-16 but not RANTES expression was dependent on the activity of caspase-3. Pro-IL-16 protein could be detected in homogenates of thyroid tissue from patients with multinodular goiter and Graves’ disease. Thus, human thyrocytes, through the expression of chemoattractants, may participate in the recruitment of lymphocytes to the thyroid in inflammatory states. (Endocrinology 144: 2856 –2864, 2003)