bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Hypervariable Region in Streptococcal M Proteins: Binding of a Human Complement Inhibitor
Authors: Johnsson Eskil , Berggård Karin , Kotarsky Heike , Hellwage Jens , Zipfel Peter F. , Sjöbring Ulf , Lindahl Gunnar 
Published: December 2022

AbstractAntigenic variation allows pathogenic microorganisms to evade the immune system of the infected host. The variable structure must play an important role in pathogenesis, but its function is in most cases unknown. Here, we identify a function for the surface-exposed hypervariable region of streptococcal M5 protein, a virulence factor that inhibits phagocytosis. The hypervariable region of M5 was found to bind the human complement inhibitor FHL-1 (factor H-like protein 1), a 42-kDa plasma protein. Plasma absorption experiments with M5-expressing bacteria showed that the interaction with FHL-1 occurs also under physiologic conditions. Studies of another extensively characterized M protein, M6, indicated that this protein also has a binding site for FHL-1 in the hypervariable region. The complement-inhibitory function of FHL-1 was retained after binding to streptococci, suggesting that bound FHL-1 protects bacteria against complement attack. All available data now indicate that FHL-1, or another human complement inhibitor, binds to the hypervariable region of M proteins. These findings provide insights into the forces that drive antigenic variation and may explain why the hypervariable region of M protein is essential for phagocytosis resistance. Moreover, these data add to a growing body of evidence that human complement inhibitors are major targets for pathogenic microorganisms.
Two Lineages of Mannose-Binding Lectin-Associated Serine Protease (MASP) in Vertebrates
Authors: Endo Yuichi , Takahashi Minoru , Nakao Miki , Saiga Hidetoshi , Sekine Hideharu , Matsushita Misao , Nonaka Masaru , Fujita Teizo 
Published: December 2022

AbstractMannose-binding lectin-associated serine protease (MASP) is a newly identified member of the serine protease superfamily. MASP is involved in host defense against pathogens through a novel system of complement activation, designated the lectin pathway. To elucidate the origin of the lectin pathway and the molecular evolution of MASP, we cloned six MASP cDNAs from five vertebrate species going from mammal to cyclostome. An alignment of the amino acid sequences deduced from the cDNAs revealed the presence of two different lineages of the MASP gene. This classification was supported by the precise correlation with two types of exon organization for the protease domain. One of the two lineages is unique in that a single exon encodes the protease domain, unlike most other serine proteases. All members of this group, termed the AGY type, have an AGY codon at the active site serine. A phylogenetic tree suggests that the AGY type diverged from another lineage, termed the TCN type, before the emergence of primitive vertebrates. Furthermore, the presence of MASP or MASP-like sequences in most vertebrate species suggests that the lectin pathway functions extensively in vertebrates and that its origin is traced back to the invertebrate stage.
Inhibition by Dexamethasone of Antigen-Induced c-Jun N-Terminal Kinase Activation in Rat Basophilic Leukemia Cells
Authors: Hirasawa Noriyasu , Sato Yukako , Fujita Yuhko , Mue Suetsugu , Ohuchi Kazuo 
Published: December 2022

AbstractAntigen stimulation of IgE-sensitized rat basophilic leukemia RBL-2H3 cells induced activation of c-Jun N-terminal kinase (JNK) within a few minutes with maximum activity attained 40 min later. The increase in JNK activity was accompanied with an increase in phosphorylation of c-Jun in the cells. The Ag-induced JNK activation was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin (10–100 nM) and LY 294002 (100 μM) but not by the protein kinase C inhibitors calphostin C (1 and 3 μM) and Ro 31-8425 (1 and 3 μM). Pretreatment with dexamethasone (10 and 100 nM) for 18 h inhibited the Ag-induced increase in JNK activity in a concentration-dependent manner. At least 6 h of preincubation with dexamethasone was necessary to inhibit the Ag-induced JNK activation. The phosphorylation of c-Jun induced by the Ag stimulation was reduced by pretreatment with dexamethasone without reduction of the content of c-Jun protein. The Ag-induced activation of the JNK kinase kinase mitogen-activated protein kinase-extracellular signal-regulated kinase kinase-1 was also inhibited by pretreatment with dexamethasone at 10 and 100 nM. These findings indicate that dexamethasone reduces JNK protein level and inhibits the Ag-induced activation of JNK resulting in the inhibition of c-Jun phosphorylation.
Induction of Cyclooxygenase-2 by Secretory Phospholipases A2 in Nerve Growth Factor-Stimulated Rat Serosal Mast Cells Is Facilitated by Interaction with Fibroblasts and Mediated by a Mechanism Independent of Their Enzymatic Functions
Authors: Tada Kinji , Murakami Makoto , Kambe Terumi , Kudo Ichiro 
Published: December 2022

AbstractMast cells exhibit a biphasic (immediate and delayed) eicosanoid-biosynthetic response after stimulation with particular cytokines or FcεRI (high affinity receptor for IgE) cross-linking. Treatment of rat serosal connective tissue mast cells (CTMC) with nerve growth factor (NGF) induced only the delayed phase of PGD2 generation that depended on inducible cyclooxygenase-2 (COX-2), but not constitutive COX-1, even though the subcellular distributions of these isoforms were similar. Experiments using several phospholipase A2 (PLA2) isozyme-specific probes and inhibitors suggested that both constitutive cytosolic PLA2 and inducible type IIA secretory PLA2 (sPLA2) are involved in NGF-initiated, COX-2-dependent, delayed PGD2 generation in rat CTMC. A type IIA sPLA2 inhibitor, but neither cytosolic PLA2 nor COX inhibitors, reduced, while adding exogenous type IIA sPLA2 augmented, NGF-induced COX-2 expression and its attendant PGD2 generation, indicating that the sPLA2-mediated increase in delayed PGD2 generation was attributable mainly to enhanced COX-2 expression. Type IIA sPLA2 and its close relative type V sPLA2 associated with fibroblastic cell surfaces increased NGF-induced COX-2 expression more efficiently than the soluble enzymes, revealing a particular juxtacrine sPLA2 presentation route. Surprisingly, catalytically inactive type IIA sPLA2 mutants, which were incapable of promoting arachidonic acid release from cytokine-primed cells, retained the ability to enhance COX-2 expression in CTMC, indicating that the COX-2-inducing activities of sPLA2 are independent of their catalytic functions.
STCP-1 (MDC) CC Chemokine Acts Specifically on Chronically Activated Th2 Lymphocytes and Is Produced by Monocytes on Stimulation with Th2 Cytokines IL-4 and IL-13
Authors: Andrew David P. , Chang Ming-shi , McNinch Jennifer , Wathen Scott T. , Rihanek Marynette , Tseng Julia , Spellberg Jason P. , Elias Chester G. 
Published: December 2022

AbstractSTCP-1 stimulated T cell chemoattractant protein-1 (STCP-1) (macrophage-derived chemokine; MDC), a recently described CC chemokine for chronically activated T lymphocytes, was found to act specifically on a subset of memory CD4 lymphocytes that displayed a Th2 cytokine profile. Also, STCP-1, thymus and activation regulated chemokine (TARC), eotaxin, and eotaxin-2 acted specifically on in vitro derived Th2 lymphocytes, while IP-10 (IFN-γ-inducible 10-kDa protein) showed some preference for Th1 lymphocytes. The corresponding receptors for eotaxin, TARC, and IP-10 are also differentially expressed on Th1 and Th2 lymphocytes. In desensitization Ca flux experiments, TARC and STCP-1 bound to a common receptor and therefore at least one chemokine receptor for STCP-1 is CCR4. STCP-1 expression is restricted to immune cells. Dendritic cells, B cells, and macrophages produce STCP-1 constitutively, while NK cells, monocytes, and CD4 lymphocytes produce STCP-1 upon appropriate stimulation. Production of STCP-1 is positively modulated by Th2 cytokines IL-4 and IL-13 but inhibited by IL-10.
Thrombin Receptor Activation Inhibits Monocyte Spreading by Induction of ETB Receptor-Coupled Nitric Oxide Release
Authors: Srivastava Kamal D. , Magazine Harold I. 
Published: December 2022

AbstractThe effect of thrombin receptor activation on monocyte conformation was evaluated using the human monocyte cell line, THP-1, and the thrombin mimetic peptide, Trap-14. Treatment of THP-1 cells with Trap-14 induced rapid rounding of ameboid cells adherent to fibronectin-coated slides, whereas cell rounding was abrogated in the presence of the nitric oxide synthase inhibitor, NG-nitro-l-arginine or the endothelin B receptor antagonist, BQ-788. Endothelin-1 (ET-1) levels in the culture supernatant increased markedly within minutes of Trap-14 exposure with a concomitant loss in cellular ET-1 immunoreactivity. Importantly, loss of ET-1 immunoreactivity was blocked by pretreatment with the vesicle translocation inhibitor, nocodazole. Trap-14 potently induced the release of NO from THP-1 cells, whereas NO release was ablated by preincubation with BQ-788. These data demonstrate that thrombin receptor activation may inhibit cellular spreading as a result of autocrine ET-1 release and subsequent endothelin B receptor-dependent NO production, and suggest that initial exposure of inflammatory cells to thrombin may limit cellular activation and recruitment.
Prevention of Th2-Like Cell Responses by Coadministration of IL-12 and IL-18 Is Associated with Inhibition of Antigen-Induced Airway Hyperresponsiveness, Eosinophilia, and Serum IgE Levels
Authors: Hofstra Claudia L. , Van Ark Ingrid , Hofman Gerard , Kool Mirjam , Nijkamp Frans P. , Van Oosterhout Antoon J. M. 
Published: December 2022

Abstract
Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this reponse is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma.
Retrovirally Transduced Bone Marrow-Derived Dendritic Cells Require CD4+ T Cell Help to Elicit Protective and Therapeutic Antitumor Immunity
Authors: De Veerman Marijke , Heirman Carlo , Van Meirvenne Sonja , Devos Sophie , Corthals Jurgen , Moser Muriel , Thielemans Kris 
Published: December 2022

Abstract
It has been extensively documented that murine dendritic cells loaded with tumor-associated Ag (TAA)-derived peptides or protein can prime Ag-specific CD8+ cytotoxic T cells in vivo and can elicit Ag-specific immunity. Optimal presentation of TAA might be achieved by retroviral transduction of DCs allowing long term and stable expression of the TAA-peptides as well as the presentation of multiple epitopes in the context of MHC class I and/or class II molecules. Here we show that retroviral transduction of bone marrow-derived dendritic cells (DCs) with chicken OVA cDNA or the reporter gene green fluorescent protein retained their potent stimulatory capacity and that the transduced DCs could process and present the endogenously expressed OVA protein. The DCs transduced with cDNA encoding native OVA protein presented OVA-derived peptides in the context of MHC class I as well as MHC class II and induced a strong Ag-specific CTL response. DCs expressing a cytosolic form of OVA presented OVA peptides only in the context of MHC class I and failed to induce an OVA-specific CTL response in vivo when they had been cultured in the absence of exogenous protein. Immunization with retrovirally transduced DCs resulted in an Ag-specific immunity and rejection of a tumor cell challenge and a significant survival advantage in tumor-bearing mice. These results obtained in this rapidly lethal tumor model suggest that DCs transduced with TAA may be useful for tumor immunotherapy and underscore the importance of the simultaneous delivery of T cell help in the development of Ag-specific cytotoxic T-cells.
CD28-Deficient Mice Are Highly Resistant to Collagen-Induced Arthritis
Authors: Tada Yoshifumi , Nagasawa Kohei , Ho Alexandra , Morito Fumiaki , Ushiyama Osamu , Suzuki Noriaki , Ohta Hideaki , Mak Tak Wah 
Published: December 2022

Abstract
CD28 provides a critical costimulatory signal in Ag-specific T cell activation. Recent studies have revealed an important role for CD28 in the development of autoimmune diseases. We have examined the role of CD28 in collagen-induced arthritis (CIA) by inducing CIA in CD28-deficient DBA/1 mice. CD28-deficient mice never developed arthritis and showed markedly decreased levels of IgG and IgM anti-type II collagen (CII) Abs. In addition, the CD28+/− mice had similar levels of IgG1 and IgG2a anti-CII Abs, whereas in the CD28-deficient mice the level of IgG1 anti-CII Abs was decreased compared with that of IgG2a. IFN-γ production by lymph node cells in response to CII was also reduced. CD28-deficient mice were either immunized four times with CII in CFA to augment Ag loading or given low doses of IL-12 to enhance Th1 type responses. Both treatments resulted in a very low incidence of CIA development and minimal disease. CD28-deficient mice developed arthritis from injection of lymph node cells from CII-immunized wild-type mice, followed by immunization with CII in CFA. Taken together, these results indicate that costimulation of CD28 cannot be replaced by repeated activation through TCR or other costimulatory molecules. Thus, CD28 plays a critical role in both cellular and humoral immunity against CII and is indispensable for the development of CIA.
A Novel Mechanism of CD4 Lymphocyte Depletion Involves Effects of HIV on Resting Lymphocytes: Induction of Lymph Node Homing and Apoptosis Upon Secondary Signaling Through Homing Receptors
Authors: Wang Liqiang , Chen Jenny J. Y. , Gelman Benjamin B. , Konig Rolf , Cloyd Miles W. 
Published: December 2022

Abstract
Recently, we reported that abortive HIV infection of resting human T lymphocytes up-regulated expression of CD62L, the receptor for homing to lymph nodes (LNs), and enhanced homing of these cells from the blood into the LNs (Wang et al., 1997, Virology 228:141). This suggested that HIV-induced homing of resting lymphocytes (which comprise &gt;98% of all lymphocytes) may be a major mechanism for the reduction of CD4+ lymphocytes in the blood of infected individuals. This mechanism also could be partially responsible for the lymphadenopathy that often develops at the same time that CD4+ lymphocytes are disappearing from the blood. In this study, we show that secondary signaling through the homing receptors (CD62L, CD44, CD11a) of abortively infected resting CD4+ T lymphocytes induced apoptosis. These signals would occur as the cells home into the LNs. Apoptosis did not occur after secondary signaling through some other receptors (CD26, CD4, CD45, and HLA class I) or in HIV-exposed resting CD8+ lymphocytes signaled through the homing receptors. These findings indicate that HIV-induced homing of resting CD4+ lymphocytes to LNs results in death of many of these cells. This was confirmed in the LNs of SCID mice that were i.v. injected with HIV-exposed resting human lymphocytes. Thus, these effects of HIV upon binding to resting CD4+ T lymphocytes, which are not permissive for HIV replication, may significantly contribute to their depletion in vivo. These findings also offer an explanation for the bystander effect observed in the LNs of AIDS patients, whereby cells not making virus are dying.
Enhanced Epidermal Langerhans Cell Migration in IL-10 Knockout Mice
Authors: Wang Binghe , Zhuang Lihua , Fujisawa Hiroshi , Shinder Gayle A. , Feliciani Claudio , Shivji Gulnar M. , Suzuki Hirotake , Amerio Paolo , Toto Paola , Sauder Daniel N. 
Published: December 2022

AbstractThe migration of epidermal Langerhans cells (LC) to lymph nodes (LN) is critical in the initiation of contact hypersensitivity (CHS) responses. Studies suggest that contact allergen-induced epidermal proinflammatory cytokines, including IL-1 and TNF-α, play important roles in promoting LC migration. Contact allergens also induce epidermal anti-inflammatory cytokines such as IL-10. Since IL-10 down-regulates proinflammatory cytokine production and inhibits CHS, we hypothesized that IL-10 might inhibit LC migration. To test this hypothesis, IL-10 knockout (KO) mice were epicutaneously sensitized with the hapten, FITC, and 24 h later hapten-bearing cells in the draining LN were examined. The number of hapten-bearing cells in the LN was significantly greater in IL-10 KO mice than in wild-type mice. The mutant mice also had an exaggerated CHS to FITC. Pretreatment with anti-TNF-α Ab or IL-1R antagonist significantly reduced the number of hapten-bearing cells in the LN, suggesting that IL-10 modulation of LC migration involves IL-1 and TNF-α. Moreover, IL-10 KO mice demonstrated a greater increase in TNF-α, IL-1α, and IL-1β mRNAs in the allergen-exposed epidermis, and keratinocytes derived from the mutant mice were able to produce higher amounts of TNF-α and IL-1α protein. These data suggest that IL-10 plays an inhibitory role in LC migration and that this effect may occur via the down-regulation of TNF-α and IL-1 production.
Redirecting Effector T Cells Through Their IL-2 Receptors
Authors: Lustgarten Joseph , Marks James , Sherman Linda A. 
Published: December 2022

AbstractFusion proteins constructed of a tumor-specific Ab joined to IL-2 (Ab-IL-2) have been used in the past to deliver cytokine directly to the site of tumor cells in vivo. These molecules mimic the activity of IL-2 and assist in activating and expanding antitumor effector cells. To enhance the cytolytic activity of CTL specific for peptide epitopes of the Her-2/neu tumor Ag presented by HLA-A*0201 molecules, a fusion protein was constructed consisting of a single chain Ab specific for Her-2/neu, linked to IL-2 (neu-Ab-IL-2). When added to a mixture of tumor cells and Her-2/neu-specific CTL, the protein was found to augment lysis of tumor cells. In addition, the hybrid molecule also promoted lysis of Her-2/neu expressing tumors by non-tumor-specific cloned T cell lines, including Th1 CD4 cells. Analysis of the mechanism of cytotoxicity revealed that the fusion protein mediates the formation of stable conjugates between T cells expressing IL-2R and tumor cells expressing Her-2/neu, resulting in lysis through the Fas-Fas ligand pathway. Lysis induction was independent of specific engagement by the TCR. When tested for its ability to enhance tumor cell eradication by Her-2/neu-specific CD8+ T cells in an adoptive transfer model in SCID mice, neu-Ab-IL-2 facilitated the elimination of tumor cells in vivo. Surprisingly, the combination of non-tumor-specific CD8+ T cells and fusion protein also induced a significant delay of tumor growth. This represents a novel approach for redirecting non-tumor-specific T cells to eliminate tumors.
Opsonic Complement Component C3 in the Solitary Ascidian,Halocynthia roretzi
Authors: Nonaka Masaru , Azumi Kaoru , Ji Xin , Namikawa-Yamada Chisato , Sasaki Makoto , Saiga Hidetosi , Dodds Alister W. , Sekine Hideharu , Homma Miwako K. , Matsushita Misao , Endo Yuichi , Fujita Teizo 
Published: December 2022

AbstractThe recent identification of two mannose-binding lectin-associated serine protease clones from Halocynthia roretzi, an ascidian, suggested the presence of a complement system in urochordates. To elucidate the structure and function of this possibly primitive complement system, we have isolated cDNA clones for ascidian C3 (AsC3) and purified AsC3 protein from body fluid. The deduced primary structure of AsC3 shows overall similarity to mammalian C3, including a typical thioester site with the His residue required for nucleophilic activation of the thioester. AsC3 has a two-subunit chain structure, and the α-chain is cleaved at a specific site near to the N terminus upon activation. Ascidian body fluid contains an opsonic activity which enhances phagocytosis of yeast by ascidian blood cells, and Ab against AsC3 inhibits this opsonic activity. These results indicate that the complement system played a pivotal role in innate immunity by enhancing phagocytosis before the emergence of the vertebrates and well ahead of the establishment of adaptive immunity, which is believed to have occurred at about the time of the appearance of cartilaginous fish.
Characterization of Human Endotoxin Lipopolysaccharide Receptor CD14 Expression in Transgenic Mice
Authors: Hetherington Christopher J. , Kingsley Paul D. , Crocicchio Francesco , Zhang Pu , Rabin Michael S. , Palis James , Zhang Dong-Er 
Published: December 2022

AbstractCD14 is a major receptor for the bacterial endotoxin LPS. Since CD14 is specifically and highly expressed on the surface of monocytic cells, it has been used as a monocyte/macrophage differentiation marker. To identify elements that are critical for the direction of the tissue-specific expression of CD14, an 80-kb genomic DNA fragment containing the coding region of the CD14 gene, as well as a considerable amount of both upstream and downstream sequence, was used to generate transgenic mice. The analysis of mice from six different founder lines demonstrated that this genomic DNA fragment was sufficient to direct human CD14 gene expression in a monocyte-specific manner among hematopoietic cells. Furthermore, the data lead us to a new finding that CD14 is highly expressed in the human liver, a primary organ involved in the acute phase response. These transgenic mice provide a useful model to analyze the biological function of human CD14.