bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Surface Colony-Stimulating Factor 1 Can Be Cleaved by TNF-α Converting Enzyme or Endocytosed in a Clathrin-Dependent Manner
Authors: Horiuchi Keisuke , Miyamoto Takeshi , Takaishi Hironari , Hakozaki Akihiro , Kosaki Naoto , Miyauchi Yoshiteru , Furukawa Mitsuru , Takito Jiro , Kaneko Hironori , Matsuzaki Kenichiro , Morioka Hideo , Blobel Carl P. , Toyama Yoshiaki 
Published: April 2014

Abstract
CSF-1 is a hemopoietic growth factor, which plays an essential role in macrophage and osteoclast development. Alternative splice variants of CSF-1 are synthesized as soluble or membrane-anchored molecules, although membrane CSF-1 (mCSF-1) can be cleaved from the cell membrane to become soluble CSF-1. The activities involved in this proteolytic processing, also referred to as ectodomain shedding, remain poorly characterized. In the present study, we examined the properties of the mCSF-1 sheddase in cell-based assays. Shedding of mCSF-1 was up-regulated by phorbol ester treatment and was inhibited by the metalloprotease inhibitors GM6001 and tissue inhibitor of metalloproteases 3. Moreover, the stimulated shedding of mCSF-1 was abrogated in fibroblasts lacking the TNF-α converting enzyme (TACE, also known as a disintegrin and metalloprotease 17) and was rescued by expression of wild-type TACE in these cells, strongly suggesting that the stimulated shedding is TACE dependent. Additionally, we observed that mCSF-1 is predominantly localized to intracellular membrane compartments and is efficiently internalized in a clathrin-dependent manner. These results indicate that the local availability of mCSF-1 is actively regulated by ectodomain shedding and endocytosis. This mechanism may have important implications for the development and survival of monocyte lineage cells.
Developmental Exposure to Noninherited Maternal Antigens Induces CD4+ T Regulatory Cells: Relevance to Mechanism of Heart Allograft Tolerance
Authors: Molitor-Dart Melanie L. , Andrassy Joachim , Kwun Jean , Kayaoglu H. Ayhan , Roenneburg Drew A. , Haynes Lynn D. , Torrealba Jose R. , Bobadilla Joseph L. , Sollinger Hans W. , Knechtle Stuart J. , Burlingham William J. 
Published: April 2014

Abstract
We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (TR) cells. We compared offspring exposed to maternal H-2d (NIMAd) with nonexposed controls. In vitro assays did not reveal any differences in T cell responses pretransplant. Adoptive transfer assays revealed lower lymphoproliferation and greater cell surface TGF-β expression on CD4+ T cells of NIMAd-exposed vs control splenocytes. NIMAd-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF-β and IL-10. Allospecific T effector cells were induced in all mice upon i.v. challenge with B6D2F1 splenocytes or a DBA/2 heart transplant, but were controlled in NIMAd-exposed mice by TR cells to varying degrees. Some (40%) NIMAd-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMAd-exposed mice had reduced T effector responses and increased Foxp3+ TR cells (CD4+CD25+Foxp3+ TR) in spleen and lymph nodes compared with controls. The key features distinguishing NIMAd-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF-β-producing cells primarily in the CD4+CD25+ T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP+, Foxp3+, and CD4+ T cells, with few CD8+ T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific TR cells during ontogeny. Their persistence in the adult, and the ability of the host to mobilize them to the graft, may determine whether NIMA-specific tolerance is achieved.
Induction of Robust Diabetes Resistance and Prevention of Recurrent Type 1 Diabetes Following Islet Transplantation by Gene Therapy
Authors: Tian Chaorui , Ansari Mohammed Javeed I. , Paez-Cortez Jesus , Bagley Jessamyn , Godwin Jonathan , Donnarumma Michela , Sayegh Mohamed H. , Iacomini John 
Published: April 2014

Abstract
We have previously shown that the development of type 1 diabetes (T1D) can be prevented in nonobese diabetic (NOD) mice by reconstitution with autologous hemopoietic stem cells retrovirally transduced with viruses encoding MHC class II I-A β-chain molecules associated with protection from the disease. In this study we examined whether a blockade of the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway, a major pathway known to control diabetes occurrence, could precipitate T1D in young NOD mice following reconstitution with autologous bone marrow retrovirally transduced with viruses encoding protective MHC class II I-A β-chain molecules. In addition, we examined whether the expression of protective MHC class II alleles in hemopoietic cells could be used to prevent the recurrence of diabetes in mice with pre-existing disease following islet transplantation. Protection from the occurrence of T1D diabetes in young NOD mice by the expression of protective MHC class II I-A β-chain molecules in bone marrow-derived hemopoietic cells was resistant to induction by PD-1-PD-L1 blockade. Moreover, reconstitution of NOD mice with pre-existing T1D autologous hemopoietic stem cells transduced with viruses encoding protective MHC class II I-A β-chains allowed for the successful transplantation of syngeneic islets, resulting in the long-term reversal of T1D. Reversal of diabetes was resistant to induction by PD-1-PDL-1 blockade and depletion of CD25+ T cells. These data suggest that expression of protective MHC class II alleles in bone marrow-derived cells establishes robust self-tolerance to islet autoantigens and is sufficient to prevent the recurrence of autoimmune diabetes following islet transplantation.
JunB Is Required for IgE-Mediated Degranulation and Cytokine Release of Mast Cells
Authors: Textor Björn , Licht Alexander H. , Tuckermann Jan P. , Jessberger Rolf , Razin Ehud , Angel Peter , Schorpp-Kistner Marina , Hartenstein Bettina 
Published: April 2014

Abstract
Mast cells are effector cells of IgE-mediated immune responses frequently found at the vicinity of blood vessels, the margins of diverse tumors and at sites of potential infection and inflammation. Upon IgE-mediated stimulation, mast cells produce and secrete a broad spectrum of cytokines and other inflammatory mediators. Recent work identified JunB, a member of the AP-1 transcription factor family, as critical regulator of basal and induced expression of inflammatory mediators in fibroblasts and T cells. To study the impact of JunB on mast cell biology, we analyzed JunB-deficient mast cells. Mast cells lacking JunB display a normal in vivo maturation, and JunB-deficient bone marrow cells in vitro differentiated to mast cells show no alterations in proliferation or apoptosis. But these cells exhibit impaired IgE-mediated degranulation most likely due to diminished expression of SWAP-70, Synaptotagmin-1, and VAMP-8, and due to impaired influx of extracellular calcium. Moreover, JunB-deficient bone marrow mast cells display an altered cytokine expression profile in response to IgE stimulation. In line with these findings, the contribution of JunB-deficient mast cells to angiogenesis, as analyzed in an in vitro tube formation assay on matrigel, is severely impaired due to limiting amounts of synthesized and secreted vascular endothelial growth factor. Thus, JunB is a critical regulator of intrinsic mast cell functions including cross-talk with endothelial cells.
Targeting IFN-α to B Cell Lymphoma by a Tumor-Specific Antibody Elicits Potent Antitumor Activities
Authors: Huang Tzu-Hsuan , Chintalacharuvu Koteswara R. , Morrison Sherie L. 
Published: April 2014

Abstract
IFN-α, a cytokine crucial for the innate immune response, also demonstrates antitumor activity. However, use of IFN-α as an anticancer drug is hampered by its short half-life and toxicity. One approach to improving IFN-α’s therapeutic index is to increase its half-life and tumor localization by fusing it to a tumor-specific Ab. In the present study, we constructed a fusion protein consisting of anti-HER2/neu-IgG3 and IFN-α (anti-HER2/neu-IgG3-IFN-α) and investigated its effect on a murine B cell lymphoma, 38C13, expressing human HER2/neu. Anti-HER2/neu-IgG3-IFN-α exhibited potent inhibition of 38C13/HER2 tumor growth in vivo. Administration of three daily 1-μg doses of anti-HER2/neu-IgG3-IFN-α beginning 1 day after tumor challenge resulted in 88% of the mice remaining tumor free. Remarkably, anti-HER2/neu-IgG3-IFN-α demonstrated potent activity against established 38C13/HER2 tumors, with complete tumor remission observed in 38% of the mice treated with three daily doses of 5 μg of the fusion protein (p = 0.0001). Ab-mediated targeting of IFN-α induced growth arrest and apoptosis of lymphoma cells contributing to the antitumor effect. The fusion protein also had a longer in vivo half-life than rIFN-α. These results suggest that IFN-α Ab fusion proteins may be effective in the treatment of B cell lymphoma.
The Aryl Hydrocarbon Receptor Is Required for Optimal Resistance to Listeria monocytogenes Infection in Mice
Authors: Shi Lewis Zhichang , Faith Nancy G. , Nakayama Yumi , Suresh Makulasiddappa , Steinberg Howard , Czuprynski Charles J. 
Published: April 2014

Abstract
The aryl hydrocarbon receptor (AhR) is part of a powerful signaling system that is triggered by xenobiotic agents such as polychlorinated hydrocarbons and polycyclic aromatic hydrocarbons. Although activation of the AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin or certain polycyclic aromatic hydrocarbons can lead to immunosuppression, there is also increasing evidence that the AhR regulates certain normal developmental processes. In this study, we asked whether the AhR plays a role in host resistance using murine listeriosis as an experimental system. Our data clearly demonstrate that AhR null C57BL/6J mice (AhR−/−) are more susceptible to listeriosis than AhR heterozygous (AhR+/−) littermates when inoculated i.v. with log-phase Listeria monocytogenes. AhR−/− mice exhibited greater numbers of CFU of L. monocytogenes in the spleen and liver, and greater histopathological changes in the liver than AhR+/− mice. Serum levels of IL-6, MCP-1, IFN-γ, and TNF-α were comparable between L. monocytogenes-infected AhR−/− and AhR+/− mice. Increased levels of IL-12 and IL-10 were observed in L. monocytogenes-infected AhR−/− mice. No significant difference was found between AhR+/− and AhR−/− macrophages ex vivo with regard to their ability to ingest and inhibit intracellular growth of L. monocytogenes. Intracellular cytokine staining of CD4+ and CD8+ splenocytes for IFN-γ and TNF-α revealed comparable T cell-mediated responses in AhR−/− and AhR+/− mice. Previously infected AhR−/− and AhR+/− mice both exhibited enhanced resistance to reinfection with L. monocytogenes. These data provide the first evidence that AhR is required for optimal resistance but is not essential for adaptive immune response to L. monocytogenes infection.
Resistin-Like Molecule β (RELMβ/FIZZ2) Is Highly Expressed in the Ileum of SAMP1/YitFc Mice and Is Associated with Initiation of Ileitis
Authors: Barnes Sean L. , Vidrich Alda , Wang Mei-Lun , Wu Gary D. , Cominelli Fabio , Rivera-Nieves Jesus , Bamias Giorgos , Cohn Steven M. 
Published: April 2014

Abstract
SAMP1/Fc mice develop spontaneous ileitis that shares many features with human Crohn’s disease. One of the earliest features of ileitis in SAMP1/Fc mice is an increase in the number of ileal goblet and intermediate cells. Resistin-like molecule β (RELMβ) is a goblet cell-specific, cysteine-rich peptide previously shown to function as part of the innate immune response. In this study, we examined the role of expression of RELMβ in the initiation of ileal inflammation in SAMP1/Fc mice. RELMβ was highly induced in the ilea of SAMP1/Fc mice beginning at age 5 wk, coincident with the histological appearance of inflammation. RELMβ was found in ileal goblet cells and some intermediate and Paneth cells. Surprisingly, RELMβ mRNA levels were significantly increased in the ilea of 80% of germ-free SAMP1/Fc mice examined compared with specific pathogen-free AKR control mice of similar age. Ileitis was observed in germfree SAMP1/Fc mice, although it was attenuated relative to specific pathogen-free SAMP1/Fc mice. These data suggest that neither the early induction of RELMβ expression nor ileal inflammation requires the presence of viable intestinal flora. Neither was the induction of RELMβ dependent on the major Th1 or Th2 cytokines. However, RELMβ stimulated naive bone marrow-derived macrophages to secrete significant amounts of TNF-α, IL-6, and RANTES. Our data suggest that RELMβ is involved in the initiation of ileitis in SAMP1/Fc mice and may act through the induction of proinflammatory cytokines from resident immune cells within the mucosa.
IL-17B and IL-17C Are Associated with TNF-α Production and Contribute to the Exacerbation of Inflammatory Arthritis
Authors: Yamaguchi Yumi , Fujio Keishi , Shoda Hirofumi , Okamoto Akiko , Tsuno Nelson H. , Takahashi Koki , Yamamoto Kazuhiko 
Published: April 2014

AbstractIL-17A is a T cell-derived proinflammatory cytokine that contributes to the pathogenesis of rheumatoid arthritis. Recently, six related molecules have been identified to form the IL-17 family, as follows: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. Whereas IL-17A and IL-17F up-regulate IL-6 in synovial fibroblasts, IL-17B and IL-17C are reported to stimulate the release of TNF-α and IL-1β from the monocytic cell line, THP-1 cell. However, their detailed function remains to be elucidated. We report in this study the effects of IL-17 family on the collagen-induced arthritis (CIA) progression by T cell gene transfer and bone marrow chimeric mice. The mRNA expressions of IL-17 family (IL-17A, IL-17B, IL-17C, and IL-17F) and their receptor (IL-17R and IL-17Rh1) genes in the arthritic paws of CIA mice were elevated compared with controls. Although IL-17A and IL-17F were expressed in CD4+ T cells, IL-17B and IL-17C were expressed in the cartilage and in various cell populations in the CIA arthritic paws, respectively. In vitro, IL-17A, IL-17B, IL-17C, and IL-17F induced TNF-α production in mouse peritoneal exudate cells. In vivo, adoptive transfer of IL-17B- and IL-17C-transduced CD4+ T cells evidently exacerbated arthritis. Bone marrow chimeric mice of IL-17B and IL-17C exhibited elevated serum TNF-α concentration and the high arthritis score upon CIA induction. Moreover, neutralization of IL-17B significantly suppressed the progression of arthritis and bone destruction in CIA mice. Therefore, not only IL-17A, but also IL-17B and IL-17C play an important role in the pathogenesis of inflammatory arthritis.
Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist
Authors: Redmond William L. , Gough Michael J. , Charbonneau Bridget , Ratliff Timothy L. , Weinberg Andrew D. 
Published: April 2014

Abstract
Several members of the TNFR superfamily, including OX40 (CD134), 4-1BB (CD137), and CD27 provide critical costimulatory signals that promote T cell survival and differentiation in vivo. Although several studies have demonstrated that OX40 engagement can enhance CD4 T cell responses, the mechanisms by which OX40-mediated signals augment CD8 T cell responses are still unclear. Previously, we and others have shown that OX40 engagement on Ag-specific CD8 T cells led to increased CD8 T cell expansion, survival, and the generation of greater numbers of long-lived memory cells. Currently, we demonstrate that provision of an OX40 agonist during the activation of naive CD8 T cells primed in vivo with either soluble or tumor-associated Ag significantly augments granzyme B expression and CD8 T cell cytolytic function through an IL-2-dependent mechanism. Furthermore, augmented CTL function required direct engagement of OX40 on the responding CD8 T cells and was associated with increased antitumor activity against established prostate tumors and enhanced the survival of tumor-bearing hosts. Thus, in the absence of danger signals, as is often the case in a tumor-bearing host, provision of an OX40 agonist can overcome defective CD8 T cell priming and lead to a functional antitumor response in vivo.
Alloimmunity to Human Endothelial Cells Derived from Cord Blood Progenitors
Authors: Suárez Yajaira , Shepherd Benjamin R. , Rao Deepak A. , Pober Jordan S. 
Published: April 2014

Abstract
There is considerable interest in exploiting circulating endothelial progenitor cells (EPCs) for therapeutic organ repair. Such cells may be differentiated into endothelial cells (ECs) in vitro and then expanded for use in tissue engineering. Vessel-derived ECs are variably immunogenic, depending upon tissue source, and it is unknown whether ECs derived from cord blood EPCs are able to initiate an allogeneic response. In this study, we compare the phenotype and alloantigenicity of human cord blood progenitor cell-derived ECs with HUVECs isolated from the same donors. Human cord blood progenitor cell-derived ECs are very similar to HUVECs in the expression of proteins relevant for alloimmunity, including MHC molecules, costimulators, adhesion molecules, cytokines, chemokines, and IDO, and in their ability to initiate allogeneic CD4+ and CD8+ memory T cell responses in vitro and in vivo. These findings have significant implications for the use of cord blood EPCs in regenerative medicine or tissue engineering.
A Hypoallergenic Vaccine Obtained by Tail-to-Head Restructuring of Timothy Grass Pollen Profilin, Phl p 12, for the Treatment of Cross-Sensitization to Profilin
Authors: Westritschnig Kerstin , Linhart Birgit , Focke-Tejkl Margarete , Pavkov Tea , Keller Walter , Ball Tanja , Mari Adriano , Hartl Arnulf , Stöcklinger Angelika , Scheiblhofer Sandra , Thalhamer Josef , Ferreira Fatima , Vieths Stefan , Vogel Lothar , Böhm Alexandra , Valent Peter , Valenta Rudolf 
Published: April 2014

Abstract
Profilins are highly cross-reactive allergens in pollens and plant food. In a paradigmatic approach, the cDNA coding for timothy grass pollen profilin, Phl p 12, was used as a template to develop a new strategy for engineering an allergy vaccine with low IgE reactivity. Non-IgE-reactive fragments of Phl p 12 were identified by synthetic peptide chemistry and restructured (rs) as a new molecule, Phl p 12-rs. It comprised the C terminus of Phl p 12 at its N terminus and the Phl p 12 N terminus at its C terminus. Phl p 12-rs was expressed in Escherichia coli and purified to homogeneity. Determination of secondary structure by circular dichroism indicated that the restructuring process had reduced the IgE-reactive α-helical contents of the protein but retained its β-sheet conformation. Phl p 12-rs exhibited reduced IgE binding capacity and allergenic activity but preserved T cell reactivity in allergic patients. IgG Abs induced by immunization of mice and rabbits with Phl p 12-rs cross-reacted with pollen and food-derived profilins. Recombinant Phl p 12-rs, rPhl p 12-rs, induced less reaginic IgE to the wild-type allergen than rPhl p 12. However, the rPhl p 12-rs-induced IgGs inhibited allergic patients’ IgE Ab binding to profilins to a similar degree as those induced by immunization with the wild type. Phl p 12-rs specific IgG inhibited profilin-induced basophil degranulation. In conclusion, a restructured recombinant vaccine was developed for the treatment of profilin-allergic patients. The strategy of tail-to-head reassembly of hypoallergenic allergen fragments within one molecule represents a generally applicable strategy for the generation of allergy vaccines.
A Critical Role of Protein Kinase Cδ Activation Loop Phosphorylation in Formyl-Methionyl-Leucyl-Phenylalanine-Induced Phosphorylation of p47phox and Rapid Activation of Nicotinamide Adenine Dinucleotide Phosphate Oxidase
Authors: Cheng Ni , He Rong , Tian Jun , Dinauer Mary C. , Ye Richard D. 
Published: April 2014

Abstract
Generation of superoxide by professional phagocytes is an important mechanism of host defense against bacterial infection. Several protein kinase C (PKC) isoforms have been found to phosphorylate p47phox, resulting in its membrane translocation and activation of the NADPH oxidase. However, the mechanism by which specific PKC isoforms regulate NADPH oxidase activation remains to be elucidated. In this study, we report that PKCδ phosphorylation in its activation loop is rapidly induced by fMLF and is essential for its ability to catalyze p47phox phosphorylation. Using transfected COS-7 cells expressing gp91phox, p22phox, p67phox, and p47phox (COS-phox cells), we found that a functionally active PKCδ is required for p47phox phosphorylation and reconstitution of NADPH oxidase. PKCβII cannot replace PKCδ for this function. Characterization of PKCδ/PKCβII chimeras has led to the identification of the catalytic domain of PKCδ as a target of regulation by fMLF, which induces a biphasic (30 and 180 s) phosphorylation of Thr505 in the activation loop of mouse PKCδ. Mutation of Thr505 to alanine abolishes the ability of PKCδ to catalyze p47phox phosphorylation in vitro and to reconstitute NADPH oxidase in the transfected COS-phox cells. A correlation between fMLF-induced activation loop phosphorylation and superoxide production is also established in the differentiated PLB-985 human myelomonoblastic cells. We conclude that agonist-induced PKCδ phosphorylation is a novel mechanism for NADPH oxidase activation. The ability to induce PKCδ phosphorylation may distinguish a full agonist from a partial agonist for superoxide production.
Extensive Characterization of IFN-Induced GTPases mGBP1 to mGBP10 Involved in Host Defense
Authors: Degrandi Daniel , Konermann Carolin , Beuter-Gunia Cornelia , Kresse Alexandra , Würthner Jan , Kurig Stefanie , Beer Sandra , Pfeffer Klaus 
Published: April 2014

Abstract
IFN-γ orchestrates a potent antimicrobial host response. However, the underlying molecular basis for this immunological defense system is largely unknown. In a systematic approach to identify IFN-γ-regulated host effector molecules, a notable number of transcripts with consensus GTP-binding motives were obtained. Further extensive transcriptome and genome analyses identified five novel family members of murine guanylate-binding proteins (mGBPs) now designated mGBP6, 7, 8, 9, and 10. Moreover, in this study, all 10 mGBP members (mGBP1–10) were extensively characterized. mGBPs are selectively up-regulated in vitro by a set of proinflammatory cytokines and TLR agonists as well as in vivo after Listeria monocytogenes and Toxoplasma gondii infection. After IFN-γ stimulation, mGBP1, 2, 3, 6, 7, and 9 are associated with intracellular Toxoplasma parasites and, interestingly, virulent Toxoplasma interfere with mGBP recruitment. Taken together, mGBPs comprise an important set of host defense molecules.