bluuebunny/crossref_metadata_2025_split huggingface dataset:
For when bacterial infections persist: Toll-like receptor-inducible direct antimicrobial pathways in macrophages
Authors: Stocks Claudia J , Schembri Mark A , Sweet Matthew J , Kapetanovic Ronan 
Published: January 2018

Abstract
Macrophages are linchpins of innate immunity, responding to invading microorganisms by initiating coordinated inflammatory and antimicrobial programs. Immediate antimicrobial responses, such as NADPH-dependent reactive oxygen species (ROS), are triggered upon phagocytic receptor engagement. Macrophages also detect and respond to microbial products through pattern recognition receptors (PRRs), such as TLRs. TLR signaling influences multiple biological processes including antigen presentation, cell survival, inflammation, and direct antimicrobial responses. The latter enables macrophages to combat infectious agents that persist within the intracellular environment. In this review, we summarize our current understanding of TLR-inducible direct antimicrobial responses that macrophages employ against bacterial pathogens, with a focus on emerging evidence linking TLR signaling to reprogramming of mitochondrial functions to enable the production of direct antimicrobial agents such as ROS and itaconic acid. In addition, we describe other TLR-inducible antimicrobial pathways, including autophagy/mitophagy, modulation of nutrient availability, metal ion toxicity, reactive nitrogen species, immune GTPases (immunity-related GTPases and guanylate-binding proteins), and antimicrobial peptides. We also describe examples of mechanisms of evasion of such pathways by professional intramacrophage pathogens, with a focus on Salmonella, Mycobacteria, and Listeria. An understanding of how TLR-inducible direct antimicrobial responses are regulated, as well as how bacterial pathogens subvert such pathways, may provide new opportunities for manipulating host defence to combat infectious diseases.
In vivo CD30 expression in human diseases with predominant activation of Th2-like T cells
Authors: D'Elios M M , Romagnani P , Scaletti C , Annunziato F , Manghetti M , Mavilia C , Parronchi P , Pupilli C , Pizzolo G , Maggi E , Del Prete G F , Romagnani S 
Published: January 2018

Abstract
CD3O is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2-type cytokines. The presence of CD3O expression was assessed by both immunohistochemistry and reverse transcriptase-polymerase chain reaction in the target organs of patients with Th1- or Th2-dominated disorders. CD3O expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori-infected patients, where there was high interferon-γ (IFN-γ) expression. In contrast, high CD3O expression in the apparent absence of IFN-γ expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2-dominated disorders. Moreover, high levels of soluble CD3O were found in the serum of both systemic sclerosis and GVHD patients but not in the serum of patients suffering from multiple sclerosis, a Th1-dominated disorder. Thus, CD3O expression appears to be preferentially associated with Th2-type responses not only in vitro but also in vivo.
Wherefore interferon?
Authors: Gresser Ion 
Published: January 2018

Abstract
Interferon (IFN) was discovered by virologists interested in the phenomenon of viral interference and for many years was considered to be exclusively an antiviral substance. In time, it was accepted that the antiviral action was only one manifestation of the multiple effects of IFN on cells. IFN was shown to inhibit the development of tumors, to modulate immune function, and even to induce disease. Some aspects of these phenomena will be discussed. Despite this plethora of biological effects of type I IFN, the potency of its antiviral action, combined with its varied effects on both the cell-mediated and humoral immune response, render it a most effective and remarkable antiviral substance. Arguments will be presented to support the hypothesis that the major role of IFN is, after all, in antiviral defense. Finally, the use of type I IFN in the treatment of patients with viral and neoplastic diseases and even diseases of varied and unknown etiology is discussed.
Coupling of neutrophil apoptosis to recognition by macrophages: coordinated acceleration by protein synthesis inhibitors
Authors: Whyte Moira K B , Savill John , Meagher Laura C , Lee Alison , Haslett Christopher 
Published: January 2018

Abstract
Onset of apoptosis in many cell types, including the neutrophil granulocyte, leads to recognition and ingestion by macrophages, a key regulatory step in clearance of inflammatory cells from inflamed sites. These studies examined the requirement for protein synthesis in neutrophil apoptosis and in the recognition of apoptotic neutrophils by monocyte-derived macrophages. Treatment with cyclohexidmide or actinomycin D produced a time- and concentration-dependent acceleration of apoptosis in populations of neutrophils purified from human peripheral blood. Both compounds caused significant promotion of apoptosis after 8 h (apoptosis was 7.7 ± 2.9%, mean ± sem, in control populations, 57.5 ± 4.9% in cycloheximide-treated, and 73.4 ± 5.5% in actmomycin D-treated populations, n = 4, P &lt; 0.001), which was associated with loss of neutrophil functional ability (assessed by shape change on N-formyl-methionyl-leucyl-phenylalanine stimulation) and increased macrophage recognition and ingestion of neutrophil populations with accelerated apoptosis. These results support the existence of survival proteins, which act as intracellular suppressors of programmed cell death. However, protein synthesis was not required for the recognition process because macrophage recognition was increased pari passu with the morphology of apoptosis.
5-Lipoxygenase inhibitors potentiate effects of TGF-β1 on the differentiation of human leukemia HL-60 cells
Authors: Kozubík Alois , Hofmanová Jirina , Dušek Ladislav , Musilová Eva 
Published: January 2018

Abstract
It was clearly demonstrated that two structurally different inhibitors of 5-lipoxygenase (5-LPO) metabolism (leukotriene synthesis), i.e. MK-886 and esculetin, when combined with transforming growth factor-β1 (TGF-β1), significantly enhanced the differentiation but did not change proliferation (i.e. cell number and cell cycle parameters) of human leukemia HL-60 cells in vitro. Although cell morphology and measurement of cell surface antigens (CD11b, CD14, and CD66b) after 48 h of combined treatment with MK-886 and TGF-β1 suggested a shift of the HL-60 cell population into more differentiated stages of myelopoiesis, cells with a fully mature phenotype were not observed. The effects on differentiation were better distinguished in the functional parameters of differentiation, i.e. oxidative burst of cells as detected by chemiluminescence and the nitroblue tetrazolium reduction test. Detailed statistical analysis of these data proved a significant synergistic interaction between TGF-β1 and inhibitors of 5-LPO metabolism. The differentiation effects of TGF-β1 alone and especially of its combination with MK-886 were most pronounced when the cells were pretreated with dimethyl sulfoxide or all-trans-retinoic acid. The results imply that either the lack of 5-LPO metabolites or a certain type of mis-balance in arachidonic acid metabolism can modulate the TGF-β1 effect on myeloid differentiation.
Differential regulation of biosynthesis of cell surface and secreted TNF-α in LPS-stimulated murine macrophages
Authors: Chaudhri Geeta 
Published: January 2018

Abstract
Activated macrophages synthesize a 26-kDa cell surface form and a 17-kDa secreted form of tumor necrosis factor α (TNF-α). This study was designed to investigate possible differences between the biosynthesis of these two forms by murine peritoneal exudate cells (PEC) and a murine macrophage cell line (RAW 264.7) stimulated with lipopolysaccharide (LPS). Both PEC and RAW 264.7 cells produced surface and secreted TNF-α in response to LPS in a dose-dependent manner. However, much lower concentrations of LPS (100 ng/mL) were needed for optimal expression of surface TNF-α than for secreted TNF-α (1 μg/mL). Furthermore, concentrations of actinomycin D that inhibit the synthesis of new mRNA and the production of secreted TNF-α did not block the expression of surface TNF-α on LPS-stimulated cells. Cycloheximide inhibited the production of both forms of TNF-α at similar concentrations. The effects, on the expression of the surface form of TNF-α, of various pharmacological agents known to inhibit the production of secreted TNF-α were studied. It was found that: (1) dexamethasone, a glucocorticoid agonist and (2) ETI and ETYA, inhibitors of lipoxygenase, had no effect on cell surface TNF-α at concentrations that inhibited secreted TNF-α. The data show that there are differences in the production of surface and secreted TNF-α and indicate that the regulation of synthesis of this protein is more complex than that suggested by a mere precursor/product relationship between the two forms.
Microorganisms and their interaction with the immune system
Authors: Kotwal Girish J 
Published: January 2018

Abstract
Microorganisms interact with the immune system in multiple ways. In an interaction between a microorganism and its host, the defense of the host does not go unchallenged. Microorganisms have for decades been suspected of possessing the capabilities of hiding from and escaping the consequences of immune surveillance. Escape mechanisms like antigenic variation, latency, and genomic integration can best be described as passive mechanisms for avoiding interaction with the host immune system, to differentiate them from the more engaging and host-directed active mechanisms of interaction. Studies of the mechanism of direct entry of viruses (HIV, measles, and enteroviruses), bacteria (streptococci and staphylococci), and parasites (Leishmania and plasmodium) into immune cells like CD4+ T cells or macrophages, as reported very recently, indicate an even more aggressive mode of interaction. This aggressive mechanism of interaction with the components of the host immune system allows the microbe not only to block the normal function of immune components on the surface of immune cells from functioning, but also to obliterate a vital immune function, cellular immunity, causing immunosuppression, e.g. the depletion of CD4+ T cells due to the entry and replication of HIV. Collectively, microorganisms have evolved various mechanisms by which they can actively block almost any cellular, humoral, or systemic immune response. One general feature of the proteins that assist microorganism to immunomodulate and actively evade host defense is their structural and therefore functional similarity to the host proteins, which they effectively mimic. Understanding the different mechanisms by which microorganisms interact with the immune system can impact the design of live vaccines as well as the development of novel therapeutic immunomodulators that can provide medicine with powerful new tools to manage immune disorders, allograft rejection, remote multiple organ failure resulting from trauma, autoimmune diseases, etc.
Humanized mAb H22 binds the human high affinity Fc receptor for IgG (FcγRI), blocks phagocytosis, and modulates receptor expression
Authors: Wallace Paul K , Keler Tibor , Coleman Kimberly , Fisher Jan , Vitale Laura , Graziano Robert F , Guyre Paul M , Fanger Michael W 
Published: January 2018

Abstract
About 10–15% of patients with immune thrombocytopenic purpura (ITP) cannot be controlled by corticosteroid therapy and splenectomy. For these patients treatment with high-dose IVIgG induces partial or complete responses. The clinical benefits of IVIgG could be due to blockade of Fc receptors for IgG (FcγR), because several model systems clearly show that functional FcγR are essential for establishment of ITP and related diseases. However, the specific contributions of the three individual classes of FcγR remain to be more completely defined. Recently monoclonal antibody (mAb) H22, which recognizes an epitope on FcγRI (CD64) outside the ligand binding domain, was humanized by grafting its complementarity determining regions onto human IgG1 constant domains. Because FcγRI has a high affinity for human IgG1 antibodies, we predicted mAb H22 would also bind to FcγRI through its Fc domain and block FcγRI-mediated phagocytosis. These studies demonstrate that mAb H22 blocked phagocytosis of opsonized red blood cells 1000 times more effectively than an irrelevant IgG. Moreover, cross-linking FcγRI with mAb H22 rapidly down-modulated FcγRI expression on monocytes without affecting other surface antigens. We conclude that because mAb H22 is a humanized mAb that blocks the FcγRI ligand binding domain and down-modulates FcγRI expression, it is a particularly good candidate for evaluating the role of FcγRI in patients with ITP.
In vitro expansion of CD13+CD33+ dendritic cell precursors from multipotent progenitors is regulated by a discrete fas-mediated apoptotic schedule
Authors: Santiago-Schwarz Frances , Borrero Michelle , Tucci John , Palaia Thomas , Carsons Steven E 
Published: January 2018

Abstract
We provide new information on how apoptosis regulates the expansion and survival of dendritic cell (DC) elements during in vitro hematopoiesis. Functionally distinct apoptotic schedules were associated with different phases of DC development when multipotent CD34+ progenitor cells were treated with GM-CSF + TNF ± SCF (c-kit ligand). During early phases of growth, unselected progenitors underwent apoptosis. During intermediate stages, high levels of apoptosis resulted in the preferential selection of DC precursors, as revealed by the massive expansion of DR+CD33+CD13+ cells. Late apoptosis was associated with the death of mature DCs. Apoptotic events surrounding the earlier periods were related to the exogenous addition of TNF-α and appeared to be mediated by fas. In contrast, those events associated with terminally differentiated DCs were fas independent because there was no correlation between fas expression and cell death. The bcl-2 protein family appeared to confer resistance to apoptotic death, as revealed by the high levels of bcl-2 and bclxL during peak DC development and in long-term DC cultures. We demonstrate that activation of distinct apoptotic programs regulates DC development and homeostasis. Although suppression of apoptosis may prolong the survival of late DC elements, an earlier apoptotic schedule appears to be required for the selective expansion of DC elements from multipotent progenitors. Our data also provides insight into the mechanism(s) of myeloid lineage selection by cytokines such as TNF-α, which may promote both cell death and survival.
Ultraviolet irradiation accelerates apoptosis in human polymorphonuclear leukocytes: protection by LPS and GM-CSF
Authors: Sweeney John F , Nguyen Phu Kim , Omann Geneva M , Hinshaw Daniel B 
Published: January 2018

Abstract
Polymorphonuclear leukocytes (PMN) play a central role in host response to injury and infection. Understanding factors that regulate PMN survival may therefore have a major influence on the development of novel treatment strategies for controlling life-threatening infections, as well as local and systemic inflammatory responses. Unfortunately, the presently utilized in vitro culture model of PMN apoptosis makes the examination of early biochemical events surrounding PMN apoptosis very difficult. This study demonstrates that a short course of UV irradiation (15 min) can be used to induce rapid progression of PMN through the apoptotic process with 70–90% of PMN displaying features of apoptosis by 4 h after UV exposure. Bacterial lipopolysaccharide and granulocyte-macrophage colony-stimulating factor, which are known to prolong PMN survival during in vitro culture, also protected PMN from UV-accelerated apoptosis. The UV-accelerated model of PMN apoptosis provides another valuable tool for the investigation of early signaling pathways associated with inducing or delaying PMN apoptosis.
Secreted poxvirus chemokine binding proteins
Authors: Lalani Alshad S , McFadden Grant 
Published: January 2018

Abstract
Poxviruses encode a variety of immunomodulatory proteins that subvert the cytokine networks of infected hosts. Myxoma virus, a poxvirus pathogen of rabbits, expresses two distinct 35- to 40-kDa secreted glycoproteins that bind a broad spectrum of chemokines. The first of these, designated M-T7, is encoded by the T7 gene and is the first example of what is here referred to as type-I chemokine binding protein (CBP-I). M-T7 was initially discovered as a secreted viral homologue of cellular interferon-γ receptor but binding studies indicate that purified M-T7 protein also interacts with members of the CXC, CC, and C chemokine families through the conserved heparin-binding domains. The second myxoma protein, M-T1, also called CBP-II, is a member of a larger superfamily of poxvirus proteins that includes related secreted 35-kDa proteins encoded by a wide variety of orthopoxviruses. Deletion analysis of either CBP-I or -II genes within recombinant poxvirus constructs revealed profound alterations in the trafficking of infiltrating leukocytes into virus-infected lesions. It is proposed that the interaction of CBP-I with the conserved heparin-binding domains found on most chemokines represents a novel mechanism for altering multiple chemokine functions in vivo. In summary, CBP-I and CBP-II are the first examples of secreted virus proteins that bind to multiple chemokine family members as part of a strategy to prevent the early phase of inflammatory cell migration into virus-infected tissues.
In vivo properties of monocyte chemoattractant protein-1
Authors: Gu Long , Rutledge Barbara , Fiorillo Joseph , Ernst Catherine , Grewal Iqbal , Flavell Richard , Gladue Ron , Rollins Barrett 
Published: January 2018

Abstract
Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes, memory T lymphocytes, and natural killer (NK) cells in vitro. Its expression has been documented in disorders characterized by mononuclear cell infiltrates, suggesting that it may contribute to the inflammatory component of such diseases as atherosclerosis, multiple sclerosis, or rheumatoid arthritis. To prove a causal association, the in vivo properties of MCP-1 must be understood. Several lines of transgenic mice have been constructed to address this question. A transgenic line in which MCP-1 expression is controlled by the MMTV-LTR expressed high levels of MCP-1 in multiple organs but showed no evidence for monocyte infiltration. Instead, these mice were more susceptible to infection by the intracellular pathogens, Listeria monocytogenes and Mycobacterium tuberculosis. These mice had high serum levels of MCP-1, suggesting that their circulating monocytes may have been desensitized or that MCP-1 stimulated a Th2-dominant response. In contrast, another model in which MCP-1 expression was controlled by the insulin promoter demonstrated a monocytic infiltrate in pancreatic islets. These results indicate that MCP-1 expression at low levels in an anatomically confined area results in monocyte infiltration, suggesting that when properly expressed, MCP-1's in vitro properties are reproduced in vivo. This justifies the examination of MCP-1-deficient mice in disease models in order to explore MCP-1's role in pathogenesis.
Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression
Authors: Luan Jing , Shattuck-Brandt Rebecca , Haghnegahdar Hamid , Owen James D , Strieter Robert , Burdick Marie , Nirodi Chaitanya , Beauchamp Dan , Johnson Kimberly Newsom , Richmond Ann 
Published: January 2018

Abstract
By reverse transcriptase-polymerase chain reaction, enzymelinked immunosorbent assay, and immunohistochemistry, MGSA-α, -β, -γ, and CXCR2 mRNA expression and proteins are detected in 7 out of 10 human melanoma lesions. The biological consequence of constitutive expression of the MGSA/GRO chemokine in immortalized melanocytes was tested in SCID and nude mouse models. Continuous expression of MGSA/GRO-α, -β, or -γ in immortalized melan-a mouse melanocytes results in nearly 100% tumor formation for each of the clones tested, whereas clones expressing only the neomycin resistance vector form tumors &lt;10% of the time. Moreover, antibodies to the MGSA/GRO proteins slow or inhibit the formation of tumors in the SCID mouse model and block the angiogenic response to conditioned medium from the tumor-producing clones. Transcription of the MGSA/ GRO chemokines is regulated by an enhancesomelike complex comprised of the nuclear factor-κB (NF-κB), HMG(I)Y, IUR, and Sp1 elements. In Hs294T melanoma cells the half life of the IκB protein is shortened in comparison to normal retinal epithelial cells, facilitating the endogenous nuclear localization of NF-κB. We propose that this endogenous nuclear NF-κB, working in concert with the 115-κDa IUR-binding factor, promotes constitutive expression of MGSA/GRO genes.
Chemokines in neurological disease models: correlation between chemokine expression patterns and inflammatory pathology
Authors: Ransohoff Richard M 
Published: January 2018

Abstract
We have recently determined chemokine expression profiles in a variety of models of neural trauma and immune-inflammation. The results indicate the following: (1) Chemokine expression in posttraumatic inflammation is generally restricted to the monocyte chemoattractant MCP-1, and occurs before hematogenous cell entry into neural tissues. Therefore MCP-1 is an excellent candidate for a mediator of leukocyte recruitment in these settings. (2) Chemokine expression in immune-inflammation is diverse and includes both α- and β-chemokines. Chemokine production can be attributed to parenchymal and infiltrating cell populations. Early signs of inflammation precede chemokine expression, which is believed to exert the crucial function of amplifying the immunemediated inflammatory reaction. These observations provide a basis for evaluating model neurological disorders in transgenic mice that express chemokines ectopically or in mice that are deficient in chemokine ligands or receptors as a consequence of gene targeting. Ultimately, a clear definition of roles of chemokines and their receptors in neurological diseases will suggest rational intervention. J.
Eotaxin influences the development of embryonic hematopoietic progenitors in the mouse
Authors: Quackenbush Elizabeth J , Aguirre Vincent , Wershil Barry K , Gutierrez-Ramos Jose Carlos 
Published: January 2018

Abstract
Eotaxin is a potent chemoattractant for eosinophils during inflammation and allergic reactions in the adult, but its role during development has not been studied. We report that eotaxin and its receptor, CCR-3, are expressed by embryonic tissues responsible for blood development, including the yolk sac, fetal liver, and fetal blood. We also found that eotaxin acts synergistically with stem cell factor (SCF) to accelerate the differentiation of embryonic mast cell progenitors and to promote the growth of Mac-1+/Gr-1- cells from progenitors isolated at 10-12 days of gestation. This response is diminished by Pertussistoxin, the Giα inhibitor. These studies suggest that eotaxin is involved in the growth of myeloid cell progenitors and the differentiation of mast cells during embryogenic development.