Publications by authors named "Tatsuro Irimura"

113 Publications

A Possible Inhibitory Role of Sialic Acid on MUC1 in Peritoneal Dissemination of Clear Cell-Type Ovarian Cancer Cells.

Molecules 2021 Oct 1;26(19). Epub 2021 Oct 1.

Division of Glycobiologics, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan.

The role of sialic acids on MUC1 in peritoneal dissemination of ovarian cancer cells was investigated. A human ovarian carcinoma cell line, ES-2, was transfected with full-length MUC1 containing 22 or 42 tandem repeats. These transfectants were less adherent to monolayers of patient-derived mesothelial cells than ES-2/mock transfectants. When these cells were inoculated into the abdominal cavity of female nude mice, mice that had received the transfectants showed better survival. When the transfectants were mixed with sialidase and injected, the survival was poorer, whereas when they were mixed with -acetyl-2,3-dehydro-2-deoxyneuraminic acid, a sialidase inhibitor, the survival was significantly prolonged. These behaviors, concerned with peritoneal implantation and dissemination observed in vitro and in vivo, were dependent on the expression of MUC1. Therefore, sialic acid linked to MUC1 in the form, at least in part, of sialyl-T, as shown to be recognized by monoclonal antibody MY.1E12, is responsible for the suppression of adhesion of these cells to mesothelial cells and the suppression of peritoneal implantation and dissemination.
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http://dx.doi.org/10.3390/molecules26195962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512441PMC
October 2021

Glycans unique to the relapse-prone subset within triple-negative breast cancer as revealed by lectin array-based analysis of surgical specimens.

PLoS One 2021 11;16(5):e0250747. Epub 2021 May 11.

Division of Glycobiologics, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Introduction: Molecular and cellular characteristics of the relapse-prone subset within triple-negative breast cancer (TNBC) remain unclear. Aberrant glycosylation is involved in the malignant behavior of cancer cells. In the present study, we aimed to reveal glycan profiles unique to relapsed TNBC patients.

Methods: Thirty TNBC patients who did not undergo neoadjuvant chemotherapy but postoperative standard adjuvant therapy from 2009 through 2016 at Juntendo Hospital were investigated. TNBC cells were resected from primary breast cancer sections of formalin-fixed surgical specimens using laser-assisted microdissection. The binding intensities of the extracted glycoproteins to 45 lectins were quantified using lectin microarray and compared between relapsed and non-relapsed patients. Immunohistochemical staining with TJA-II lectin in specimen sections was performed.

Results: Five patients relapsed during the follow-up (range 37-123 months). Lectin microarray analysis revealed that 7 out of 45 lectins showed significant differences in binding intensity between the relapsed and the non-relapsed group. TJA-II, ACA, WFA, and BPL showed stronger binding in the relapsed group. PNGase F treatment of TNBC cell lysates suggested that TJA-II and ACA bind O-glycans. TJA-II staining of tissue sections revealed strong binding to cell surface membranes and to the cytoplasm of TNBC cells, but not to other types of cells. Significantly more TNBC cells were stained in tissue sections from relapsed than non-relapsed patients.

Conclusions: TNBC cells from relapsed patients showed a unique lectin reactivity, with higher levels of TJA-II (also WFA and BPL) binding than in non-relapsed patients. The results are potentially useful to develop new prognostic and therapeutic tools.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250747PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112657PMC
October 2021

Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells.

J Biochem 2021 Oct;170(3):317-326

Division of Glycobiologics, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan.

Mesothelioma is a highly aggressive tumour associated with asbestos exposure and is histologically classified into three types: epithelioid-type, sarcomatoid-type and biphasic-type. The prognosis of mesothelioma patients is poor and there is no effective molecular-targeting therapy as yet. ERC/mesothelin is a glycoprotein that is highly expressed on several types of cancers including epithelioid mesothelioma, but also expressed on normal mesothelial cells. This is a predicted reason why there is no clinically approved therapeutic antibody targeting ERC/mesothelin. In the present study, we focussed on the differential glycosylation between ERC/mesothelin present on epithelioid mesothelioma and that on normal mesothelial cells and aimed to reveal a distinct feature of epithelioid mesothelioma cells. Lectin microarray analysis of ERC/mesothelin using cells and patient specimens showed significantly stronger binding of PHA-E4 lectin, which recognizes complex-type N-glycans having a so-called bisecting-GlcNAc structure, to ERC/mesothelin from epithelioid mesothelioma cells than that from normal mesothelial cells. Further, liquid chromatography/mass spectrometry analysis on ERC/mesothelin from epithelioid mesothelioma cells confirmed the presence of a bisecting-GlcNAc attached to Asn388 of ERC/mesothelin. These results suggest that this glycoproteome could serve as a potential target for the generation of a highly selective and safe therapeutic antibody for epithelioid mesothelioma.
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http://dx.doi.org/10.1093/jb/mvab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510291PMC
October 2021

Intestinal lamina propria macrophages upregulate interleukin-10 mRNA in response to signals from commensal bacteria recognized by MGL1/CD301a.

Glycobiology 2021 Aug;31(7):827-837

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Ligand-induced cellular signaling involved in interleukin 10 (IL-10) production by lamina propria macrophages (LPMs) during their interactions with commensal bacteria is not clearly understood. We previously showed, using mice lacking a C-type lectin MGL1/CD301a, that this molecule on colonic LPMs plays an important role in the induction of IL-10 upon interaction with commensal bacteria, Streptococcus sp. In the present report, we show that the physical engagement of MGL1/CD301a on LPMs with in-situ isolated Streptococcus sp. bacteria leads to IL-10 messenger RNA (mRNA) induction. Spleen tyrosine kinase (Syk), caspase recruitment domain 9 (CARD9) and extracellular signal-regulated kinase (ERK), but not NF-κB pathway, are shown to be indispensable for IL-10 mRNA induction after stimulation with heat-killed Streptococcus sp. Guanidine hydrochloride treatment of Streptococcus sp., which is known to extract bacterial cell surface glycan-rich components, abolished bacterial binding to recombinant MGL1/CD301a. The extract contained materials which bound rMGL1 in ELISA and appeared to induce IL-10 mRNA expression in LPMs in vitro. Lectin blotting showed that the extract contained glycoproteins that are considered as putative ligands for MGL1. Some human commensal Lactobacillus species also induced IL-10 mRNA expression by colonic LPMs in vitro, which depends on the presence of MGL1/CD301a and CARD9. The present results are the first to show that MGL1/CD301a acts as a signal transducer during colonic host-microbe interactions.
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http://dx.doi.org/10.1093/glycob/cwab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351502PMC
August 2021

Biological and Clinicopathological Implications of Beta-3-N-acetylglucosaminyltransferase 8 in Triple-negative Breast Cancer.

Anticancer Res 2021 Feb;41(2):845-858

Division of Glycobiologics, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan;

Background/aim: Triple-negative breast cancer (TNBC) remains difficult to treat and new molecular targets are needed. Here, we investigated the impact of glycosyltransferase genes on TNBC patient survival.

Patients And Methods: mRNA expression levels of 101 glycosyltransferase genes in TNBC patients were compared for correlation with patient survival using The Cancer Genome Atlas data. An antibody to β-3-N-acetylgluco-saminyltransferase 8 (B3GNT8) was applied to investigate B3GNT8 protein distribution and expression levels in 23 TNBC surgical specimens.

Results: B3GNT8 mRNA levels inversely correlated with relapse-free survival (p<0.01) and overall survival (p<0.05) in TNBC patients. Anti-B3GNT8 antibody binding was observed as dots in the cytoplasm of cancer cells. These dots were supposed to correspond to B3GNT8 protein in tumour cells, but their number was smaller in relapsed patients than in non-relapsed patients.

Conclusion: B3GNT8 mRNA expression levels in TNBC tumour tissues are potentially useful in distinguishing patients with favourable and poor clinical outcomes.
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http://dx.doi.org/10.21873/anticanres.14837DOI Listing
February 2021

Heparanase is Involved in Leukocyte Migration.

Adv Exp Med Biol 2020 ;1221:435-444

SBI Pharmaceuticals Co., Ltd, Minato-ku, Tokyo, Japan.

Leukocyte migration is essential for exerting self-defense mechanisms. During the extravasation process, leukocytes transmigrate through the endothelial lining and the subendothelial basement membrane. Accumulating evidence supports the involvement of heparanase in this process. Altered cellular distribution resulting in relocalization of heparanase to the leading edge of migration is a key event to rapidly turn on the function of the enzyme during migration. This review presents current research investigating the cellular machinery that builds up a functional subcellular structure for leukocyte attachment to and degradation of the extracellular matrix. Recent advances in the understanding of the roles of heparanase in inflammatory diseases and pharmacological approaches to control heparanase-mediated actions during inflammation are also discussed.
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http://dx.doi.org/10.1007/978-3-030-34521-1_16DOI Listing
July 2020

Clec10a regulates mite-induced dermatitis.

Sci Immunol 2019 12;4(42)

Department of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

House dust mite (HDM) is a major allergen that causes allergic diseases such as atopic dermatitis. However, the regulatory mechanisms of HDM-induced immune responses are incompletely understood. NC/Nga mice are an inbred strain that is more susceptible to HDM and develops more severe dermatitis than other strains. Using whole-exome sequencing, we found that NC/Nga mice carry a stop-gain mutation in , which encodes a C-type lectin receptor, Clec10a (MGL1/CD301a). The repair of this gene mutation using the CRISPR-Cas9 system ameliorated HDM-induced dermatitis, indicating that the Clec10a mutation is responsible for hypersensitivity to HDM in NC/Nga mice. Similarly, mice on the C57BL/6J background showed exacerbated HDM-induced dermatitis. Clec10a expressed on skin macrophages inhibits HDM-induced Toll-like receptor 4 (TLR4)-mediated inflammatory cytokine production through the inhibitory immunoreceptor tyrosine activating motif in its cytoplasmic portion. We identified asialoglycoprotein receptor 1 (Asgr1) as a functional homolog of mouse Clec10a in humans. Moreover, we found that a mucin-like molecule in HDM is a ligand for mouse Clec10a and human Asgr1. Skin application of the ligand ameliorated a TLR4 ligand-induced dermatitis in mice. Our findings suggest that Clec10a in mice and Asgr1 in humans play an important role in skin homeostasis against inflammation associated with HDM-induced dermatitis.
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http://dx.doi.org/10.1126/sciimmunol.aax6908DOI Listing
December 2019

Products of Chemoenzymatic Synthesis Representing MUC1 Tandem Repeat Unit with T-, ST- or STn-antigen Revealed Distinct Specificities of Anti-MUC1 Antibodies.

Sci Rep 2019 11 12;9(1):16641. Epub 2019 Nov 12.

Division of Glycobiologics, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Anti-mucin1 (MUC1) antibodies have long been used clinically in cancer diagnosis and therapy and specific bindings of some of them are known to be dependent on the differential glycosylation of MUC1. However, a systematic comparison of the binding specificities of anti-MUC1 antibodies was not previously conducted. Here, a total of 20 glycopeptides including the tandem repeat unit of MUC1, APPAHGVTSAPDTRPAPGSTAPPAHGV with GalNAc (Tn-antigen), Galβ1-3GalNAc (T-antigen), NeuAcα2-3Galβ1-3GalNAc (sialyl-T-antigen), or NeuAcα2-6GalNAc (sialyl-Tn-antigen) at each threonine or serine residue were prepared by a combination of chemical glycopeptide synthesis and enzymatic extension of carbohydrate chains. These glycopeptides were tested by the enzyme-linked immunosorbent assay (ELISA) for their capacity to bind 13 monoclonal antibodies (mAbs) known to be specific for MUC1. The results indicated that anti-MUC1 mAbs have diverse specificities but can be classified into a few characteristic groups based on their binding pattern toward glycopeptides in some cases having a specific glycan at unique glycosylation sites. Because the clinical significance of some of these antibodies was already established, the structural features identified by these antibodies as revealed in the present study should provide useful information relevant to their further clinical use and the biological understanding of MUC1.
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http://dx.doi.org/10.1038/s41598-019-53052-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851390PMC
November 2019

Chondroitin sulfate E blocks enzymatic action of heparanase and heparanase-induced cellular responses.

Biochem Biophys Res Commun 2019 11 1;520(1):152-158. Epub 2019 Oct 1.

Division of Glycobiologics, Intractable Disease Research Center, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

We examined whether chondroitin sulfates (CSs) exert inhibitory effects on heparanase (Hpse), the sole endoglycosidase that cleaves heparan sulfate (HS) and heparin, which also stimulates chemokine production. Hpse-mediated degradation of HS was suppressed in the presence of glycosaminoglycans derived from a squid cartilage and mouse bone marrow-derived mast cells, including the E unit of CS. Pretreatment of the chondroitin sulfate E (CS-E) with chondroitinase ABC abolished the inhibitory effect. Recombinant proteins that mimic pro-form and mature-form Hpse bound to the immobilized CS-E. Cellular responses as a result of Hpse-mediated binding, namely, uptake of Hpse by mast cells and Hpse-induced release of chemokine CCL2 from colon carcinoma cells, were also blocked by the CS-E. CS-E may regulate endogenous Hpse-mediated cellular functions by inhibiting enzymatic activity and binding to the cell surface.
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http://dx.doi.org/10.1016/j.bbrc.2019.09.126DOI Listing
November 2019

Mucin 21 is a key molecule involved in the incohesive growth pattern in lung adenocarcinoma.

Cancer Sci 2019 Sep 16;110(9):3006-3011. Epub 2019 Aug 16.

Department of Integrative Pathology, Jichi Medical University, Japan.

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.
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http://dx.doi.org/10.1111/cas.14129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726699PMC
September 2019

Specific expression of MUC21 in micropapillary elements of lung adenocarcinomas - Implications for the progression of EGFR-mutated lung adenocarcinomas.

PLoS One 2019 11;14(4):e0215237. Epub 2019 Apr 11.

Department of Pathology, Yokohama City University, School of Medicine, Yokohama, Japan.

We investigated the significance of MUC21 in EGFR-mutated lung adenocarcinoma (LADC). Two-hundred forty-one surgically resected LADCs (116 EGFR-mutated and 125 wild-type tumors) were examined for immunohistochemical expression of MUC21 protein. A polyclonal antibody and two monoclonal antibodies (heM21C and heM21D) that bind differentially glycosylated MUC21 epitopes were used, and MUC21 proteins detected by these antibodies were named MUC21P, MUC21C, and MUC21D, respectively. MUC21 mRNA levels were semi-quantified and classified into "high" and "low". Among the immunohistochemical expression detected by three different antibodies, high expressors tended to be related to EGFR mutations. The three varieties of the immunohistochemical expressions were related to different histological elements in the EGFR-mutated LADCs. Either MUC21P or MUC21C high expressors had a higher proportion of lepidic elements with low papillary structure and micropapillary elements. MUC21D high expressors had a significantly higher proportion of micropapillary elements (Mann-Whitney test P ≤0.0001). Furthermore, MUC21D high expressors showed high incidence of lymphatic canal invasion and lymph node metastasis (Pearson x2 test, P = 0.0021, P = 0.0125), and a significantly higher recurrence rate (5-year recurrence-free survival 50.7% vs. 73.8%, log-rank test P = 0.0495). MUC21 proteins with a specific glycosylation status may be involved in the progression of EGFR-mutated LADCs, particularly at the stage where tumors are transforming from pure lepidic to micropapillary through low papillary lepidic lesions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215237PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459478PMC
January 2020

Incorporation, intracellular trafficking and processing of extracellular heparanase by mast cells: Involvement of syndecan-4-dependent pathway.

Biochem Biophys Res Commun 2018 09 24;503(4):3235-3241. Epub 2018 Aug 24.

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Division of Glycobiologics, Intractable Disease Research Center, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 104-8520, Japan.

We investigated the fate of proheparanase added to the culture media of mast cells. A recombinant protein mimicking proheparanase was continuously internalized into mastocytoma cells as well as bone marrow- and peritoneal cell-derived mast cells. Internalized heparanase molecules were accumulated in granules and a significant portion was released by stimulation with ionomycin, indicating that the internalized heparanase was sorted into secretory granules. The pro-form heparanase was processed into a mature and an active form inside the cells, in which intracellular heparin was fragmented by the mature enzyme. The internalization was substantially inhibited by addition of heparin and heparan sulfate to the culture medium, suggesting that glycosaminoglycan is involved in the uptake pathway. Out of four syndecans, expression of syndecan-3 and syndecan-4, especially cell surface syndecan-4, was detected in the mastocytoma cells. Two knockdown clones transfected with a shRNA expression vector targeting the syndecan-4 gene took up significantly lower amounts of heparanase than mock cells. We propose that some exogenous substances like proheparanase can be incorporated into mast cell granules via a glycosaminoglycan-mediated, especially syndecan-4-dependent, uptake pathway.
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http://dx.doi.org/10.1016/j.bbrc.2018.08.132DOI Listing
September 2018

A Critical Domain of Ebolavirus Envelope Glycoprotein Determines Glycoform and Infectivity.

Sci Rep 2018 04 3;8(1):5495. Epub 2018 Apr 3.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.

Ebolaviruses comprises 5 species that exert varying degrees of mortality/infectivity in humans with Reston ebolaviruses (REBOV) showing the lowest and Zaire ebolaviruses (ZEBOV) showing the highest. However, the molecular basis of this differential mortality/infectivity remains unclear. Here, we report that the structural features of ebolavirus envelope glycoproteins (GPs) and one of their counter receptors, macrophage galactose-type calcium-type lectin (MGL/CD301), play crucial roles in determining viral infectivity. The low infectivity of REBOV mediated by the interaction between GPs and MGL/CD301 dramatically increased when the N-terminal 18 amino acids (33rd through 50th) of GPs were replaced with that of ZEBOV. Furthermore, structural analysis of glycans of GPs revealed that N-glycans were more extended in REBOV than in ZEBOV. N-glycan extension was reversed by the replacement of aforementioned N-terminal 18 amino acid residues. Therefore, these data strongly suggest that extended N-glycans on GPs reduce MGL/CD301-mediated viral infectivity by hindering the interaction between GPs and MGL/CD301 preferentially binds O-glycans.
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http://dx.doi.org/10.1038/s41598-018-23357-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882653PMC
April 2018

Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology.

J Antibiot (Tokyo) 2017 Nov 1. Epub 2017 Nov 1.

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.

Microbial metabolites have attracted increasing interest as a source of therapeutics and as probes for biological mechanisms. New microbial metabolites and derivatives targeted at inflammation and bone disease therapy have been identified by focusing on prostaglandin release, osteoblast differentiation and immune cell functions. These modulators of inflammatory processes and bone disease contribute to our understanding of biological mechanisms and support identification of the therapeutic potential of drug lead candidates. The present review describes recent advances in the chemistry and analysis of inhibitors of prostaglandin release or other functional molecules of immune cells, as well as inducers of osteoblast differentiation, including biological and pharmacological activities.The Journal of Antibiotics advance online publication, 1 November 2017; doi:10.1038/ja.2017.138.
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http://dx.doi.org/10.1038/ja.2017.138DOI Listing
November 2017

Proteasome Inhibitor-Loaded Micelles Enhance Antitumor Activity Through Macrophage Reprogramming by NF-κB Inhibition.

J Pharm Sci 2017 09 12;106(9):2438-2446. Epub 2017 Apr 12.

Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; Policy Alternatives Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address:

Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.
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http://dx.doi.org/10.1016/j.xphs.2017.03.031DOI Listing
September 2017

IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression.

Cancer Sci 2016 Sep 1;107(9):1206-14. Epub 2016 Sep 1.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL-17A was critical for amplifying such local inflammation, as observed in the production of IL-1β and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23-dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30(+) Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.
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http://dx.doi.org/10.1111/cas.13005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021032PMC
September 2016

An iminosugar-based heparanase inhibitor heparastatin (SF4) suppresses infiltration of neutrophils and monocytes into inflamed dorsal air pouches.

Int Immunopharmacol 2016 Jun 22;35:15-21. Epub 2016 Mar 22.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Biochemistry, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan; Department of Breast and Endocrine Surgery, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan. Electronic address:

Local infiltration of inflammatory cells is regulated by a number of biological steps during which the cells likely penetrate through subendothelial basement membranes that contain heparan sulfate proteoglycans. In the present study, we examined whether administration of heparastatin (SF4), an iminosugar-based inhibitor of heparanase, could suppress local inflammation and degradation of heparan sulfate proteoglycans in basement membranes. In a carrageenan- or formyl peptide-induced dorsal air pouch inflammation model, the number of infiltrated neutrophils and monocytes was significantly lower in mice after topical administration of heparastatin (SF4). The concentration of chemokines MIP-2 and KC in pouch exudates of drug-treated mice was similar to control. In a zymosan-induced peritonitis model, the number of infiltrated cells was not altered in drug-treated mice. To further test how heparastatin (SF4) influences transmigration of inflammatory neutrophils, its suppressive effect on migration and matrix degradation was examined in vitro. In the presence of heparastatin (SF4), the number of neutrophils that infiltrated across a Matrigel-coated polycarbonate membrane was significantly lower, while the number of neutrophils passing through an uncoated membrane was not altered. Lysate of bone marrow-derived neutrophils released sulfate-radiolabeled macromolecules from basement membrane-like extracellular matrix, which was suppressed by heparastatin (SF4). Heparan sulfate degradation activity was almost completely abolished after incubation of lysate with protein G-conjugated anti-heparanase monoclonal antibody, strongly suggesting that the activity was due to heparanase-mediated degradation. Taken together, in a dorsal air pouch inflammation model heparastatin (SF4) potentially suppresses extravasation of inflammatory cells by impairing the degradation of basement membrane heparan sulfate.
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http://dx.doi.org/10.1016/j.intimp.2016.03.017DOI Listing
June 2016

Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs.

Cancer Sci 2016 Feb;107(2):189-202

Subcommittee on Non-clinical Studies, The Science Board to the Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs.
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http://dx.doi.org/10.1111/cas.12857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768389PMC
February 2016

Heparanase augments inflammatory chemokine production from colorectal carcinoma cell lines.

Biochem Biophys Res Commun 2016 Jan 20;469(4):878-83. Epub 2015 Dec 20.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Biochemistry and Department of Breast and Endocrine Surgery, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan. Electronic address:

To explore possible roles of heparanase in cancer-host crosstalk, we examined whether heparanase influences expression of inflammatory chemokines in colorectal cancer cells. Murine colorectal carcinoma cells incubated with heparanase upregulated MCP-1, KC, and RANTES genes and released MCP-1 and KC proteins. Heparanase-dependent production of IL-8 was detected in two human colorectal carcinoma cell lines. Addition of a heparanase inhibitor Heparastatin (SF4) did not influence MCP-1 production, while both latent and mature forms of heparanase augmented MCP-1 release, suggesting that heparanase catalytic activity was dispensable for MCP-1 production. In contrast, addition of heparin to the medium suppressed MCP-1 release in a dose-dependent manner. Similarly, targeted suppression of Ext1 by RNAi significantly suppressed cell surface expression of heparan sulfate and MCP-1 production in colon 26 cells. Taken together, it is concluded that colon 26 cells transduce the heparanase-mediated signal through heparan sulfate binding. We propose a novel function for heparanase independent of its endoglycosidase activity, namely as a stimulant for chemokine production.
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http://dx.doi.org/10.1016/j.bbrc.2015.12.074DOI Listing
January 2016

POMGNT1 Is Glycosylated by Mucin-Type O-Glycans.

Biol Pharm Bull 2015 ;38(9):1389-94

Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology.

Protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is a Golgi glycosyltransferase that catalyzes the formation of the N-acetylglucosamine (GlcNAc) β1→2Man linkage of O-mannosyl glycan. POMGNT1 is not modified by N-glycans because there are no potential N-glycosylation sites; however, it is not clear whether POMGNT1 is modified by O-glycans. To determine whether POMGNT1 is O-glycosylated, we prepared recombinant human POMGNT1 from HEK293T cells. The recombinant POMGNT1 was recognized by Sambucus sieboldiana lectin (SSA), and sialidase digestion of POMGNT1 decreased SSA reactivity and enhanced the reactivity of Arachis hypogaea lectin (PNA). These results suggest that POMGNT1 is modified by a sialylated core-1 O-glycan. Next, we analyzed the structures of the O-glycans on POMGNT1 by β-elimination and pyrazolone-labeling methods in combination with mass spectrometry. We identified several mucin-type O-glycans containing (NeuAc)1(Hex)1(HexNAc)1, (NeuAc)2(Hex)1(HexNAc)1, and (NeuAc)2(Hex)2(HexNAc)2. To examine whether the O-glycans affect the functions and properties of POMGNT1, we compared glycosylated and non-glycosylated forms of recombinant sPOMGNT1 for their activity and surface hydrophobicity using the hydrophobic probe 1-anilino-8-naphthalene sulfonate (ANS). POMGNT1 activity and surface hydrophobicity were not affected by the presence or absence of O-glycans.
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http://dx.doi.org/10.1248/bpb.b15-00415DOI Listing
June 2016

Lectin Microarray-Based Sero-Biomarker Verification Targeting Aberrant O-Linked Glycosylation on Mucin 1.

Anal Chem 2015 Jul 7;87(14):7274-81. Epub 2015 Jul 7.

†Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 2, 1-1-1, Umezono, Tsukuba, Ibaraki 305-8568, Japan.

Glycoform of mucin 1 (MUC1) in cancerous cells changes markedly with cell differentiation, and thus, qualitative detection and verification of the MUC1 glycosylation changes have potential diagnostic value. We have developed an ultrasensitive method to detect the changes in cholangiocarcinoma (CC), which produces MUC1, and applied it in the diagnostics development. The focused glycan analysis using 43-lectin-immobilized microarray could obtain the glycan profiles of sialylated MUC1 in 5 μL of sera. The high-throughput analysis detected disease-specific alterations of glycosylation, and the statistical analysis confirmed that use of Wisteria floribunda agglutinin (WFA) alone produced a diagnostic score sufficient for discriminating 33 CC cases from 40 hepatolithiasis patients and 48 normal controls (p < 0.0001). The CC-related glycosylation change was verified by the lectin-antibody sandwich ELISA with WFA in two cohorts: (1) 78 Opisthorchis viverrini infected patients without CC and 78 with CC, (2) 33 CC patients and 40 hepatolithiasis patients (the same cohort used for the above lectin microarray). The WFA positivity distinguished patients with CC (opisthorchiasis: p < 0.0001, odds ratio = 1.047; hepatolithiasis: p = 0.0002, odds ratio = 1.018). Sensitive detection of qualitative alterations of sialylated MUC1 glycosylation is indispensable for the development of our glycodiagnostic test for CC.
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http://dx.doi.org/10.1021/acs.analchem.5b01329DOI Listing
July 2015

Mammary tissue microenvironment determines T cell-dependent breast cancer-associated inflammation.

Cancer Sci 2015 Jul 29;106(7):867-74. Epub 2015 May 29.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Although the importance of the host tissue microenvironment in cancer progression and metastasis has been established, the spatiotemporal process establishing a cancer metastasis-prone tissue microenvironment remains unknown. In this study, we aim to understand the immunological character of a metastasis-prone microenvironment in a murine 4T1 breast tumor model, by using the activation of nuclear factor-κb (NF-κB) in cancer cells as a sensor of inflammatory status and by monitoring its activity by bioluminescence imaging. By using a 4T1 breast cancer cell line stably expressing an NF-κB/Luc2 reporter gene (4T1 NF-κB cells), we observed significantly increased bioluminescence approximately 7 days after metastasis-prone orthotopic mammary fat-pad inoculation but not ectopic s.c. inoculation of 4T1 NF-κB cells. Such in vivo NF-κB activation within the fat-pad 4T1 tumor was diminished in immune-deficient SCID or nude mice, or T cell-depleted mice, suggesting the requirement of host T cell-mediated immune responses. Given the fat-pad 4T1 tumor expressed higher inflammatory mediators in a T cell-dependent mechanism compared to the s.c. tumor, our results imply the importance of the surrounding tissue microenvironment for inflaming tumors by collaborating with T cells to instigate metastatic spread of 4T1 breast cancer cells.
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http://dx.doi.org/10.1111/cas.12685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520638PMC
July 2015

CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.

BMC Cancer 2014 Dec 15;14:949. Epub 2014 Dec 15.

Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Background: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients.

Methods: We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages.

Results: CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis.

Conclusions: Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.
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http://dx.doi.org/10.1186/1471-2407-14-949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300614PMC
December 2014

Identification of Hirsutine as an anti-metastatic phytochemical by targeting NF-κB activation.

Int J Oncol 2014 Nov 27;45(5):2085-91. Epub 2014 Aug 27.

Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.

Nuclear factor-κB (NF-κB) activation has been implicated not only in carcinogenesis but also in cancer cell invasion and metastatic process; therefore, targeting the NF-κB pathway is an attractive strategy for controlling meta-stasis. Amongst 56 chemically defined compounds derived from natural products, we have identified a new phytochemical compound Hirsutine, which strongly suppresses NF-κB activity in murine 4T1 breast cancer cells. In accordance with the NF-κB inhibition, Hirsutine reduced the metastatic potential of 4T1 cells, as seen in the inhibition of the migration and invasion capacity of 4T1 cells. Hirsutine further inhibited the constitutive expression of MMP-2 and MMP-9 in 4T1 cells, and reduced the in vivo lung metastatic potential of 4T1 cells in the experimental model. Given that the migration of human breast cancer cells was also inhibited, our present study implies that Hirsutine is an attractive phytochemical compound for reducing metastasis potential of cancer cells by regulating tumor-promoting NF-κB activity.
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http://dx.doi.org/10.3892/ijo.2014.2624DOI Listing
November 2014

Interaction of Muc4 and ErbB2 in a transgenic mouse model of gallbladder carcinoma: potential pathobiological implications.

Oncol Rep 2014 Nov 25;32(5):1796-802. Epub 2014 Aug 25.

Institute for Medical Innovation, St. Luke's International Medical Center, Chuo-ku, Tokyo, Japan.

The molecular mechanism of gallbladder carcinogenesis and cancer growth remains unknown. BK5.erbB2 transgenic mice in which erbB2 is overexpressed and activated in the biliary epithelia develop adenocarcinoma of the gallbladder at a high incidence. Although it has been reported that erbB2 plays an important role in tumorigenesis, little is known about the involvement of its ligand(s). The expression level of Muc4, a potential functional ligand for erbB2, and its interaction with erbB2 in the gallbladder of BK5.erbB2 mice were determined. By immunohistochemistry and in situ hybridization, both Muc4 mRNA and protein levels were strongly expressed in the cancerous epithelia of gallbladder from BK5.erbB2 mice. Also, in the hyperplastic (precancerous) epithelia, the protein levels were modestly expressed. Immunostaining with Muc4 (ASGP2) Ab overlapped with that with erbB2 Ab in the apical membranous components of the cancerous epithelia, indicating the co-localization of Muc4 and erbB2. Immunoprecipitation experiments revealed an interaction between Muc4 and erbB2 in the gallbladders. The interaction was associated with the hyperphosphorylation of erbB2, MAPK and Akt, and also with the overexpression of cyclooxygenase-2. However, in other organs that overexpressed erbB2 (trachea, esophagus and forestomach), Muc4 was expressed in only trace or modest amounts, and erbB2 was not hyperphosphorylated. Collectively, Muc4 is upregulated and interacts with erbB2 in gallbladders from BK5.erbB2 mice. It is likely that Muc4 plays an important role during gallbladder carcinogenesis and/or cancer growth by potentiating erbB2 signaling.
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http://dx.doi.org/10.3892/or.2014.3443DOI Listing
November 2014

Up-regulation of neogenin-1 increases cell proliferation and motility in gastric cancer.

Oncotarget 2014 May;5(10):3386-98

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Although elevated expression of neogenin-1 has been detected in human gastric cancer tissue, its role in gastric tumorigenesis remains unclear due to the lack of neogenin-1 studies in cancer. Therefore, we demonstrated here the function and regulatory mechanism of neogenin-1 in gastric cancer. Neogenin-1 ablation decreased proliferation and migration of gastric cancer cells, whereas its over-expression reversed these effects. Xenografted analyses using gastric cancer cells displayed statistically significant inhibition of tumor growth by neogenin-1 depletion. Interestingly, galectin-3 interacted with HSF-1 directly, which facilitated nuclear-localization and binding on neogenin-1 promoter to drive its transcription and gastric cancer cell motility. The galectin-3-increased gastric cancer cell motility was down-regulated by HSF-1 depletion. Moreover, the parallel expression patterns of galectin-3 and neogenin-1, as well as those of HSF-1 and neogenin-1, were detected in the malignant tissues of gastric cancer patients. Taken together, high-expression of neogenin-1 promotes gastric cancer proliferation and motility and its expression is regulated by HSF-1 and galectin-3 interaction. In addition, we propose further studies for neogenin-1 and its associated pathways to provide them as a proper target for gastric cancer therapy.
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http://dx.doi.org/10.18632/oncotarget.1960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102817PMC
May 2014

Heparanase-mediated cleavage of macromolecular heparin accelerates release of granular components of mast cells from extracellular matrices.

Biochem J 2014 Mar;458(2):291-9

*Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

Heparanase cleaves macromolecular heparin in the secretory granules of connective tissue-type mast cells. We investigated roles of the cleavage under a microenvironment mimicking where the mast cells physiologically reside. A connective tissue-type mast cell line MST and mouse peritoneal cell-derived mast cells stored macromolecular heparin in the secretory granules. The cells expressing heparanase stored fragmented heparin (~10 kDa) due to heparanase-dependent cleavage of the heparin. We produced an artificial collagen-based extracellular matrix and placed the live cells or glycosaminoglycans purified from the cells in the matrix to measure the release of sulfated macromolecules into the medium. The sulfate-radiolabelled molecules from the degranulating heparanase-expressing cells and the purified glycosaminoglycans showed significantly greater release into the medium than those derived from mock cells, which was not the case in suspension culture. The mast cell granular enzyme chymase, but not β-hexosaminidase, showed significantly greater release from the degranulating heparanase-expressing cells than from mock cells. Purified chymase mixed with fragmented heparin derived from heparanase-expressing cells showed greater release from collagen gels than the enzyme alone or mixed with macromolecular heparin derived from mock cells. We propose that the cleavage of macromolecular heparin by heparanase accelerates the release of heparin and chymase from extracellular matrices.
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http://dx.doi.org/10.1042/BJ20131463DOI Listing
March 2014

The macrophage galactose-type lectin can function as an attachment and entry receptor for influenza virus.

J Virol 2014 Feb 20;88(3):1659-72. Epub 2013 Nov 20.

Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia.

Specific protein receptors that mediate internalization and entry of influenza A virus (IAV) have not been identified for any cell type. Sialic acid (SIA), the primary attachment factor for IAV hemagglutinin, is expressed by numerous cell surface glycoproteins and glycolipids, confounding efforts to identify specific receptors involved in virus infection. Lec1 Chinese hamster ovary (CHO) epithelial cells express cell surface SIA and bind IAV yet are largely resistant to infection. Here, we demonstrate that expression of the murine macrophage galactose-type lectin 1 (MGL1) by Lec1 cells enhanced Ca(2+)-dependent IAV binding and restored permissivity to infection. Lec1 cells expressing MGL1 were infected in the presence or absence of cell surface SIA, indicating that MGL1 can act as a primary receptor or as a coreceptor with SIA. Lec1 cells expressing endocytosis-deficient MGL1 mediated Ca(2+)-dependent IAV binding but were less sensitive to IAV infection, indicating that direct internalization via MGL1 can result in cellular infection. Together, these studies identify MGL1 as a cell surface glycoprotein that can act as an authentic receptor for both attachment and infectious entry of IAV.
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http://dx.doi.org/10.1128/JVI.02014-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911607PMC
February 2014

A unique dermal dendritic cell subset that skews the immune response toward Th2.

PLoS One 2013 9;8(9):e73270. Epub 2013 Sep 9.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan.

Dendritic cell (DC) subsets in the skin and draining lymph nodes (LNs) are likely to elicit distinct immune response types. In skin and skin-draining LNs, a dermal DC subset expressing macrophage galactose-type C-type lectin 2 (MGL2/CD301b) was found distinct from migratory Langerhans cells (LCs) or CD103(+) dermal DCs (dDCs). Lower expression levels of Th1-promoting and/or cross-presentation-related molecules were suggested by the transcriptome analysis and verified by the quantitative real-time PCR analysis in MGL2(+) dDCs than in CD103(+) dDCs. Transfer of MGL2(+) dDCs but not CD103(+) dDCs from FITC-sensitized mice induced a Th2-type immune response in vivo in a model of contact hypersensitivity. Targeting MGL2(+) dDCs with a rat monoclonal antibody against MGL2 efficiently induced a humoral immune response with Th2-type properties, as determined by the antibody subclass. We propose that the properties of MGL2(+) dDCs, are complementary to those of CD103(+) dDCs and skew the immune response toward a Th2-type response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073270PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767795PMC
June 2014
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