bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Protein Kinase C-α in the Control of Infection by Intracellular Pathogens in Macrophages
Authors: St-Denis Anik , Caouras Vassiliki , Gervais Francine , Descoteaux Albert 
Published: December 2022

AbstractThe protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In this study, we investigated the role of macrophage PKC-α in the uptake and subsequent fate of Leishmania donovani promastigotes and Legionella pneumophila infections. To this end, we used clones of the murine macrophage cell line RAW 264.7 overexpressing a dominant-negative (DN) mutant of PKC-α. While phagocytosis of L. donovani promastigotes was not affected by DN PKC-α overexpression, their intracellular survival was enhanced by 10- to 20-fold at 48 h postinfection. Intracellular survival of a L. donovani mutant defective in lipophosphoglycan repeating units synthesis, which normally is rapidly degraded in phagolysosomes, was enhanced by 100-fold at 48 h postinfection. However, IFN-γ-induced leishmanicidal activity was not affected by DN PKC-α overexpression. Similar to macrophages from genetically resistant C57BL/6 mice, control RAW 264.7 cells were not permissive for the intracellular replication of Legionella pneumophila. In contrast, DN PKC-α-overexpressing RAW 264.7 clones were phenotypically similar to macrophages from genetically susceptible A/J mice, as they allowed intracellular replication of L. pneumophila. Permissiveness to L. pneumophila was not the consequence of a general defect in the microbicidal capacities because killing of a temperature-sensitive mutant of Pseudomonas aeruginosa was normal in DN PKC-α-overexpressing RAW 264.7 clones. Collectively, these results support a role for PKC-α in the regulation of innate macrophage functions involved in the control of infection by intracellular parasites.
Impaired Anti-Viral T Cell Responses Due to Expression of the LY49A Inhibitory Receptor
Authors: Zajac Allan J. , Vance Russell E. , Held Werner , Sourdive David J. D. , Altman John D. , Raulet David H. , Ahmed Rafi 
Published: December 2022

Abstract
Inhibitory receptors specific for alleles of MHC class I proteins play an important role in determining the reactivity and specificity of NK cells. To determine whether these receptors are also able to regulate T cell functions, we have studied anti-viral immune responses in mice transgenic for a class I-specific inhibitory receptor, Ly49A. Although nontransgenic mice express Ly49A primarily on NK cells and some T cells, the Ly49A transgenic mice express Ly49A on all lymphocytes, including T cells. We have assessed the activation, expansion, cytokine production, and cytotoxic activity of CD8 T cells in both transgenic and nontransgenic mice following infection with lymphocytic choriomeningitis virus. As expected, nontransgenic mice made a potent virus-specific CD8 T cell response following virus infection. However, as measured in cytolysis assays and by cytokine production, virus-specific CD8 T cell activity was reduced in Ly49A transgenic mice. This inhibition was largely, but not always exclusively, dependent upon the presence, either in vivo or in vitro, of the Ly49A ligand, H-2Dd. Strikingly Ly49A transgenic mice have reduced capacity to control infection with the virulent lymphocytic choriomeningitis virus variant clone 13. Overall, these studies demonstrate that expression of killer inhibitory receptors can modulate anti-viral T cell responses in vivo and in vitro.
Activation of T Cells Recognizing an Epitope of Heat-Shock Protein 70 Can Protect Against Rat Adjuvant Arthritis
Authors: Tanaka Shigehisa , Kimura Yuki , Mitani Akio , Yamamoto Genta , Nishimura Hitoshi , Spallek Ralf , Singh Mahavir , Noguchi Toshihide , Yoshikai Yasunobu 
Published: December 2022

AbstractWe have previously reported that CD4+ T cells recognizing a peptide comprising residues 234–252 of the heat shock protein (HSP)70 of Mycobacterium tuberculosis (M.tb) in the context of RT1.B MHC class II molecule emerged in the peritoneal cavity during the course of Listeria monocytogenes infection in rats and suppressed the inflammatory responses against listerial infection via IL-10 production. We report in this work that pretreatment with peptide 234–252 of HSP70 derived from M.tb suppressed the development of adjuvant arthritis (AA) in Lewis rats induced using heat-killed M.tb. T cells from rats pretreated with peptide 234–252 produced a significant amount of IL-10 in response to the epitope. T cells from rats pretreated with the peptide and immunized with M.tb produced the larger amount of IL-10 in response to the peptide, but only a marginal level of IFN-γ in response to purified protein derivative of M.tb. Administration of anti-IL-10 Ab partly inhibited the suppressive effect of pretreatment with peptide 234–252 on the development of AA. Furthermore, transfer of a T cell line specific for the epitope at the time of AA induction markedly suppressed AA. These findings suggested that T cells recognizing peptide 234–252 may play a regulatory role in inflammation during AA via the production of suppressive cytokines including IL-10.
Chemicals in Diesel Exhaust Particles Generate Reactive Oxygen Radicals and Induce Apoptosis in Macrophages
Authors: Hiura Timothy S. , Kaszubowski Martin P. , Li Ning , Nel Andre E. 
Published: December 2022

Abstract
There is increasing evidence that particulate air pollutants, such as diesel exhaust particles (DEP), potentiate chronic inflammatory processes as well as acute symptomatic responses in the respiratory tract. The mechanisms of action as well as the cellular targets for DEP remain to be elucidated. We show in this paper that the phagocytosis of DEP by primary alveolar macrophages or macrophage cell lines, RAW 264.7 and THP-1, leads to the induction of apoptosis through generation of reactive oxygen radicals (ROR). This oxidative stress initiates two caspase cascades and a series of cellular events, including loss of surface membrane asymmetry and DNA damage. The apoptotic effect on macrophages is cell specific, because DEP did not induce similar effects in nonphagocytic cells. DEP that had their organic constituents extracted were no longer able to induce apoptosis or generate ROR. The organic extracts were, however, able to induce apoptosis. DEP chemicals also induced the activation of stress-activated protein kinases, which play a role in cellular apoptotic pathways. The injurious effects of native particles or DEP extracts on macrophages could be reversed by the antioxidant, N-acetyl-cysteine. Taken together, these data suggest that organic compounds contained in DEP may exert acute toxic effects via the generation of ROR in macrophages.
Identification of CD66a and CD66b as the Major Galectin-3 Receptor Candidates in Human Neutrophils
Authors: Feuk-Lagerstedt Elisabeth , Jordan Elizabeth T. , Leffler Hakon , Dahlgren Claes , Karlsson Anna 
Published: December 2022

Abstract
The mammalian lectin galectin-3 is a potent stimulus of human neutrophils, provided that the receptor(s) for the lectin has been mobilized to the cell surface before activation. We have recently shown that the receptors for galectin-3 are stored in intracellular mobilizable granules. Here we show supportive evidence for this in that DMSO-differentiated (neutrophil-like) HL-60 cells, which lack gelatinase and specific granules, are nonresponsive when exposed to galectin-3. Neutrophil granules were subsequently used for isolation of galectin-3 receptors by affinity chromatography. Proteins eluted from a galectin-3-Sepharose column by lactose were analyzed on SDS-polyacrylamide gels and showed two major bands of 100 and 160 kDa and a minor band of 120 kDa. By immunoblotting, these proteins were shown to correspond to CD66a (160 kDa), CD66b (100 kDa), and lysosome-associated membrane glycoprotein-1 and -2 (Lamp-1 and -2; 120 kDa). The unresponsive HL-60 cells lacked the CD66 Ags but contained the Lamps, implying that neutrophil CD66a and/or CD66b may be the functional galectin-3 receptors. This conclusion was supported by the subcellular localization of the CD66 proteins to the gelatinase and specific granules in resting neutrophils.
The Antiinflammatory Sesquiterpene Lactone Parthenolide Inhibits NF-κB by Targeting the IκB Kinase Complex
Authors: Hehner Steffen P. , Hofmann Thomas G. , Dröge Wulf , Schmitz M. Lienhard 
Published: December 2022

Abstract
The transcription factor NF-κB is a key regulator of the cellular inflammatory and immune response. Therefore, components of the NF-κB-activating signaling pathways are frequent targets for antiinflammatory agents. This study shows that the sesquiterpene lactone parthenolide inhibits a common step in NF-κB activation by preventing the TNF-α-induced induction of IκB kinase (IKK) and IKKβ, without affecting the activation of p38 and c-Jun N-terminal kinase. Parthenolide impairs NF-κB-dependent transcription triggered by expression of TNFR-associated factor-2, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEKK1), and NF-κB-inducing kinase. This compound also prevents activation of both IKKs and DNA binding of NF-κB induced by MEKK and NF-κB-inducing kinase. Parthenolide targets a component of the IκB kinase complex without directly inhibiting IKKα, IKKβ, or MEKK1. Therefore, this sesquiterpene lactone could serve as a lead compound for the development of antiinflammatory remedies and is suitable as a molecular tool, allowing the dissection of TNF-α-derived signaling pathways leading to the activation of NF-κB, c-Jun N-terminal kinase, and p38.
Production of Metalloproteinase-7 (Matrilysin) by Human Myeloma Cells and Its Potential Involvement in Metalloproteinase-2 Activation
Authors: Barillé Sophie , Bataille Régis , Rapp Marie-José , Harousseau Jean-Luc , Amiot Martine 
Published: December 2022

Abstract
Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor spreading. Multiple myeloma (MM) is a plasma cell malignancy primarily localized within the bone marrow and characterized by its capacity to destroy bone matrix and to disseminate. We have reported recently that human myeloma cells were able to induce the conversion of pro-MMP-2 produced by the tumoral environment in its activated form. In the current study, we have investigated the mechanism involved in this process. We demonstrate that a soluble MMP constitutively produced by myeloma cells was responsible for pro-MMP-2 activation. Furthermore, we show that the soluble MMP, MMP-7, also known as matrilysin, was able to activate the MMP-2 produced in its latent form by bone marrow stromal cells. Finally, we demonstrate that myeloma cells constitutively produce MMP-7 with expected proteolytic activity. Our results suggest that MMP-7 produced by myeloma cells could participate in bone destruction and tumor spreading in MM, on one hand by its own proteolytic activity and on the other hand by its capacity to activate pro-MMP-2. These findings strengthen the idea that inhibition of MMP activity could represent an interesting therapeutic approach in MM.
A New Role for Platelet-Endothelial Cell Adhesion Molecule-1 (CD31): Inhibition of TCR-Mediated Signal Transduction
Authors: Newton-Nash Debra K. , Newman Peter J. 
Published: December 2022

AbstractPlatelet-endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kDa transmembrane glycoprotein expressed by endothelial cells, platelets, monocytes, neutrophils, and certain T cell subsets. The PECAM-1 extracellular domain has six Ig-homology domains that share sequence similarity with cellular adhesion molecules. The PECAM-1 cytoplasmic domain contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) that, when appropriately engaged, becomes phosphorylated on tyrosine residues, creating docking sites for nontransmembrane, Src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-1 and SHP-2. The purpose of the present study was to determine whether PECAM-1 inhibits protein tyrosine kinase (PTK)-dependent signal transduction mediated by the immunoreceptor tyrosine-based activation motif-containing TCR. Jurkat cells, which coexpress PECAM-1 and the TCR/CD3 complex, were INDO-1AM-labeled and then incubated with anti-CD3ε mAbs, anti-PECAM-1 mAbs, or both, and goat anti-mouse IgG was used to cross-link surface-bound mAbs. Calcium mobilization induced by CD3 cross-linking was found to be attenuated by coligation of PECAM-1 in a dose-dependent manner. PECAM-1-mediated inhibition of TCR signaling was attributable, at least in part, to inhibition of release of calcium from intracellular stores. These data provide evidence that PECAM-1 can dampen signals transduced by ITAM-containing receptors and support inclusion of PECAM-1 within the family of ITIM-containing inhibitors of PTK-dependent signal transduction.
Diacylglycerol Kinase Inhibition Prevents IL-2-Induced G1 to S Transition Through a Phosphatidylinositol-3 Kinase-Independent Mechanism
Authors: Flores Ignacio , Jones David R. , Ciprés Angel , Díaz-Flores Ernesto , Sanjuan Miguel Angel , Mérida Isabel 
Published: December 2022

AbstractStimulation via IL-2R ligation causes T lymphocytes to transit through the cell cycle. Previous experiments by our group have demonstrated that, in human T cells, IL-2 binding induces phosphatidic acid production through activation of the α isoform of diacylglycerol kinase. In this study, using the IL-2-dependent mouse T cell line CTLL-2, we demonstrate that pharmacological inhibition of IL-2-induced diacylglycerol kinase activation is found to block IL-2-induced late G1 to S transition without affecting cell viability. Herein, we demonstrate that diacylglycerol kinase inhibition has a profound effect on the induction of the protooncogenes c-myc, c-fos, and c-raf by IL-2, whereas expression of bcl-2 and bcl-xL are not affected. When the IL-2-regulated cell cycle control checkpoints are examined in detail, we demonstrate that inhibition of diacylglycerol kinase activation prevents IL-2 induction of cyclin D3 without affecting p27 down-regulation. The strict control of cell proliferation exerted by phosphatidic acid through activation of diacylglycerol kinase is independent of other well-characterized IL-2R-derived signals, such as the phosphatidylinositol-3 kinase/Akt pathway, indicating the existence of a different and important mechanism to control cell division.
Antigen Concentration and Precursor Frequency Determine the Rate of CD8+ T Cell Tolerance to Peripherally Expressed Antigens
Authors: Morgan David J. , Kreuwel Huub T. C. , Sherman Linda A. 
Published: December 2022

Abstract
Expression of transgene-encoded proteins in the pancreatic islets can cause peripheral deletion of T cells. However, tolerance has not been observed in all transgenic models. It has been proposed that the determining factor for successful peripheral tolerance is the amount of Ag cross-presented by quiescent APCs. Using InsHA mice, which demonstrate peripheral tolerance to the influenza virus hemagglutinin (HA) expressed in the pancreatic islet β cells, we have investigated the consequences when different amounts of HA are expressed. As compared with InsHA mice that are heterozygous for the InsHA transgene, homozygous InsHA mice demonstrated enhanced activation and proliferation of Kd-restricted HA-specific CD8+ T cells in the pancreatic lymph nodes. However, despite such activation, insulitis was not observed, and the T cells were gradually functionally deleted. Deletion of these activated cells occurred much more rapidly in homozygous than in heterozygous InsHA mice. These data demonstrate that there is a direct correlation between the amount of HA expressed in the periphery, and both the degree of T cell proliferation in the pancreatic lymph nodes and the rate of tolerance of HA-specific CD8+ T cells. This strongly supports the hypothesis that activation of T cells through cross-presentation of peripheral Ags in a noninflammatory environment is an important part of the normal mechanism of tolerance to Ags expressed in the pancreatic islets.
TCR and IL-12 Receptor Signals Cooperate to Activate an Individual Response Element in the IFN-γ Promoter in Effector Th Cells
Authors: Zhang Feng , Nakamura Tetsuo , Aune Thomas M. 
Published: December 2022

AbstractIFN-γ is a key regulatory cytokine of the immune system. Reporter transgenic mice expressing the luciferase gene under the control of separate TCR-response elements (TCR-RE) from the IFN-γ promoter or expressing the green fluorescent protein gene under the control of an IFN-γ “minigene” were employed to explore the basis for IL-12 regulation of IFN-γ gene transcription. In the absence of TCR stimulation, IL-12 did not activate the TCR-REs but did induce green fluorescent protein expression. TCR plus IL-12R stimulation of effector Th cells resulted in: 1) enhanced activation of the proximal, but not the distal, TCR-RE, and 2) increased induction of cJun-proximal TCR-RE complexes and c-Jun protein expression. Overexpression of cJun, but not cFos, increased activity of the proximal TCR-RE in T cells. These results suggest that IL-12R signaling affects IFN-γ gene transcription by at least two separate mechanisms; IL-12R signaling without TCR signaling targets promoter regions outside of the ∼100-bp IFN-γ TCR-RE, and IL-12R signaling also stimulates TCR-induced activity of the proximal TCR-RE.
M1204, a Novel 2′,5′ Oligoadenylate Synthetase with a Ubiquitin-Like Extension, Is Induced During Maturation of Murine Dendritic Cells
Authors: Tiefenthaler Martin , Marksteiner Rainer , Neyer Susanne , Koch Franz , Hofer Susanne , Schuler Gerold , Nussenzweig Michel , Schneider Rainer , Heufler Christine 
Published: December 2022

Abstract
A novel molecule expressed by spleen dendritic cells (DC) was isolated using a subtractive hybridization approach. The full-length M1204 clone has 3063 bp, with 1415 bp spanning a single open reading frame, coding for a protein of a predicted size of about 50 kDa. This sequence has strong homology to 2′, 5′ oligoadenylate synthetase and contains a ubiquitin-like domain. In Northern blot analyses the mRNA is strongly expressed in spleen DC, whereas, in bone marrow-derived DC, the amount of mRNA increases during the maturation process. None of the other leukocytes nor several hemopoietic cell lines tested express this mRNA, but clear expression occurs in many organs, the highest levels being in thymus, lung, and bone marrow. In situ hybridization, combined with immunocytochemical staining of tissue sections of lung and spleen, shows colocalization of M1204 with the 2A1 and NLDC DC markers. In Western blot experiments, an antiserum raised against the recombinant M1204 recognizes a single band in bone marrow-derived DC and in the lung. The expressed oligoadenylate synthetase domain is active in synthesizing 2′,5′ diadenylate, which by itself may inhibit viral protein synthesis and may also function as a substrate for 2′,5′ oligoadenylate synthetase. Since the oligoadenylate/RNase L system provides early protection against virus infection, we hypothesize that M1204 prevents virus-induced cell death in DC.
A Novel Lyn-Binding Peptide Inhibitor Blocks Eosinophil Differentiation, Survival, and Airway Eosinophilic Inflammation1, 2
Authors: Adachi Tetsuya , Stafford Susan , Sur Sanjiv , Alam Rafeul 
Published: December 2022

AbstractReceptor antagonists block all receptor-coupled signaling pathways indiscriminately. We introduce a novel class of peptide inhibitors that is designed to block a specific signal from a receptor while keeping other signals intact. This concept was tested in the model of IL-5 signaling via Lyn kinase. We have previously mapped the Lyn-binding site of the IL-5/GM-CSF receptor common β (βc) subunit. In the present study, we designed a peptide inhibitor using the Lyn-binding sequence. The peptide was N-stearated to enable cellular internalization. The stearated peptide blocked the binding of Lyn to the βc receptor and the activation of Lyn. The lipopeptide did not affect the activation of Janus kinase 2 or its association with βc. The inhibitor blocked the Lyn-dependent functions of IL-5 in vitro (e.g., eosinophil differentiation from stem cells and eosinophil survival). It did not affect eosinophil degranulation. When applied in vivo, the Lyn-binding peptide significantly inhibited airway eosinophil influx in a mouse model of asthma. The lipopeptide had no effect on basophil histamine release or on the proliferation of B cells and T cells. To our knowledge, this is the first report on an inhibitor of IL-5 that blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. This novel strategy to develop peptide inhibitors can be applied to other receptors.
Cutting Edge: RANTES Regulates Fas Ligand Expression and Killing by HIV-Specific CD8 Cytotoxic T Cells
Authors: Hadida Fabienne , Vieillard Vincent , Mollet Lucile , Clark-Lewis Ian , Baggiolini Marco , Debré Patrice 
Published: December 2022

Abstract
Based on the previous observation that RANTES mediates the cytotoxic activity of human HIV-specific CD8+ T cells via the chemokine receptor CCR3, we studied the effect of this chemokine on different effector CD8+ cytolytic cells requiring Fas/Fas ligand (FasL) or perforin-dependent pathway. In CTLs derived from PBMCs of HIV-infected patients, both the spontaneous and the RANTES-induced cytotoxicity were inhibited by anti-FasL neutralizing Abs. In contrast, allogeneic CTLs or NK cells killing through perforin were not affected by RANTES and anti-FasL Ab. Accordingly, RANTES enhanced the expression of FasL in a concentration- and time-dependent manner in HIV-specific CTLs, whereas anti-RANTES Ab decreased markedly FasL expression. Finally, cell surface expression of FasL protein in HIV-specific CTLs was also up-regulated by eotaxin, a selective ligand for CCR3. Our observations show that the action of RANTES via CCR3 is necessary to regulate FasL expression on HIV-specific CD8+ T cells that kill through the Fas/FasL pathway.
IL-18 Inhibits Diabetes Development in Nonobese Diabetic Mice by Counterregulation of Th1-Dependent Destructive Insulitis
Authors: Rothe Helga , Hausmann Andreas , Casteels Kristina , Okamura Hakuri , Kurimoto Masashi , Burkart Volker , Mathieu Chantal , Kolb Hubert 
Published: December 2022

AbstractThe development of type 1 diabetes in animal models is T cell and macrophage dependent. Islet inflammation begins as peripheral benign Th2 type insulitis and progresses to destructive Th1 type insulitis, which is driven by the innate immune system via secretion of IL-12 and IL-18. We now report that daily application of IL-18 to diabetes-prone female nonobese diabetic mice, starting at 10 wk of age, suppresses diabetes development (p &lt; 0.001, 65% in sham-treated animals vs 33% in IL-18-treated animals by 140 days of age). In IL-18-treated animals, we detected significantly lower intraislet infiltration (p &lt; 0.05) and concomitantly an impaired progression from Th2 insulitis to Th1-dependent insulitis, as evidenced from IFN-γ and IL-10 mRNA levels in tissue. The deficient progression was probably due to lesser mRNA expression of the Th1 driving cytokines IL-12 and IL-18 by the innate immune system (p &lt; 0.05). Furthermore, the mRNA expression of inducible NO synthase, a marker of destructive insulitis, was also not up-regulated in the IL-18-treated group. IL-18 did not exert its effect at the levels of islet cells. Cultivation of islets with IL-18 affected NO production or mitochondrial activity and did not protect from the toxicity mediated by IL-1β, TNF-α, and IFN-γ. In conclusion, we show for the first time that administration of IL-18, a mediator of the innate immune system, suppresses autoimmune diabetes in nonobese diabetic mice by targeting the Th1/Th2 balance of inflammatory immune reactivity in the pancreas.