bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms regulating macrophage-induced nitric oxide production by spontaneously transformed hamster fibroblasts
Authors: Lavnikova Natasha , Prokhorova Svetlana , Burdelia Ludmila , Lakhotia Anand , Laskin Debra L 
Published: January 2018

Abstract
Nitric oxide has been implicated as an important effector molecule involved in tumor cell growth and cytotoxicity. In these studies we examined mechanisms regulating nitric oxide production by hamster tumor cells. Cocultures of hamster alveolar macrophages (HAM) and spontaneously transformed hamster embryonic fibroblasts (STHE cells) produced significant quantities of nitric oxide in response to lipopolysaccharide (LPS). Culture supernatants from HAM treated with LPS also stimulated nitric oxide production by STHE cells, whereas tumor cell culture supernatants had no effect on HAM. These data, together with the findings that paraformaldehyde treatment of STHE cells, but not macrophages, completely abrogated nitric oxide production in the cocultures demonstrate that the tumor cells were the source of this mediator. In contrast to STHE cells, STHE-83/20 cells, a highly malignant variant, did not produce nitric oxide in response to HAM or HAM culture supernatants even in the presence of LPS. Both anti-tumor necrosis factor-α (TNF-α) and antiinterleukin-1α (IL-1α) antibodies inhibited HAM-induced nitric oxide production by STHE cells. However, the kinetics of their effects were different. Moreover, although the nitric oxide stimulating activity in HAM culture supernatants was abrogated by anti-TNF-α antibody, it was only minimally reduced by anti-IL-1α antibody. These data demonstrate that TNF-α and IL-1α play distinct roles in induction of nitric oxide synthesis in STHE cells. HAM were also found to suppress proliferation of STHE cells, an effect that was inhibited by anti-TNF-α antibody, but not NG-monomethyl-l-arginine, which blocks nitric oxide synthase. Abrogation of macrophage-induced cytostasis in STHE cells by anti-TNF-α antibody was associated with decreased nitric oxide production. Thus TNF-α released by macrophages may indirectly activate STHE cells for nitric oxide synthesis by suppressing tumor cell proliferation.
Activation of Src-family tyrosine kinases during Fas-induced apoptosis
Authors: Schlottmann Klaus E , Gulbins Erich , Lau Sey M , Coggeshall K Mark 
Published: January 2018

Abstract
Stimulation of several human and murine hematopoietically derived cell lines with anti-Fas antibodies induced increased tyrosine phosphorylation of a panel of proteins observed in whole-cell lysates. In the human T cell line Jurkat, the activity of a 56-kDa tyrosine kinase was likewise activated by anti-Fas antibodies. Immunoprecipitation studies of anti-Fas-stimulated human Jurkat and murine 2B4.11 T cells revealed activation of the Src-family tyrosine kinases Lck and Fyn. Fas receptor-induced tyrosine phosphorylation of p120 c-cbl proto-oncogene product was observed in Jurkat T cells. Pharmacological experiments demonstrated that pretreatment of Jurkat cells with tyrphostins inhibited Fas-induced apoptosis; likewise, Lck activity was inhibited by tyrphostins in a dose-dependent fashion. Finally, Lck derived from unstimulated Jurkat T cells formed stable complexes with the intracellular domain of the Fas receptor. These data are consistent with the notion that expression and activation of members of the Src-family kinases is required for Fas-induced cell death in T lymphocytes and consistent with recent findings demonstrating decreased Fas-mediated thymocytic death in Fyn-knockout mice.
Pro-inflammatory cytokines in lung and blood during steroid-induced Pneumocystis carinii pneumonia in rats
Authors: Perenboom Roos M , Beckers Pieter , van Der Meer Jos W M , van Schijndel Anita C H W , Oyen Wim J G , Corstens Frans H M , Sauerwein Robert W 
Published: January 2018

Abstract
To gain more insight into the role of cytokines in Pneumocystis carinii pneumonia (PCP) we followed pro-inflammatory cytokine profiles in rats with steroid-induced PCP at 2-week intervals. The cytokines measured were immunoreactive interleukin-1β (IL-lβ), bioactive interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). In vivo cytokine concentrations were determined in three compartments, i.e., bronchoalveolar lavage (BAL) fluid, lung homogenatee, and plasma. Lipopotysaccharide (LPS) -stimulated cytokine production by alveolar cells and in whole-blood cultures was measured ex vivo.
Analysis of leukocyte activation during acute rejection of pulmonary allografts in noninfected and cytomegalovirus-infected rats
Authors: Steinmüller Christiane , Steinhoff Gustav , Bauer Dirk , You Xiao-Mang , Denzin Heike , Franke-Ullmann Gabriela , Hausen Bernard , Bruggemann Cathrien , Wagner T O F , Lohmann-Matthes Maria-Luise , Emmendörffer Andreas 
Published: January 2018

Abstract
After human lung transplantation acute rejection and cytomegalovirus (CMV) infections may occur, probably contributing to the development of chronic rejection. We established a model of subacute allograft rejection in rats to analyze leukocyte activation and effects of a CMV infection. Histoincompatible lung transplants (BN/LEW) without immunosuppression (group A) and lungs of initially immunosuppressed animals (group B) were analyzed. The production of inflammatory mediators (interleukin-6, tumor necrosis factor α, nitric oxides) and the expression of MHC class II antigens by alveolar and lung tissue macrophages were significantly enhanced during the alloresponse. In recipients without immunosuppression (group A) allograft necrosis was detected by day 6, whereas group B allografts were fully rejected by day 25. In allografts of immunosuppressed, CMV-infected animals (group C) the CMV infection was clearly aggravated and the number of activated lung tissue macrophages was increased when compared with noninfected allografts or isografts. The subacute model provides the advantage of allowing us to study mechanisms of acute rejection without the effects of reperfusion injury. Furthermore these findings underline the role of inflammatory mediators produced by macrophages during rejection.
Regulation of T cell-dependent and -independent IL-12 production by the three Th2-type cytokines IL-10, IL-6, and IL-4
Authors: Takenaka Hiroshi , Maruo Seiji , Yamamoto Norihiko , Wysocka Maria , Ono Shiro , Kobayashi Michiko , Yagita Hideo , Okumura Ko , Hamaoka Toshiyuki , Trinchieri Giorgio , Fujiwara Hiromi 
Published: January 2018

Abstract
The production of IL-12 by macrophages/dendritic cells (Mɸ/DC) is mediated either by a T cell-dependent pathway that is induced primarily by the interaction of CD40 ligand (CD40L) on activated T cells with CD40 on IL-12-producing cells or by a T cell-independent pathway that is induced by bacteria or bacterial products and enhanced by interferon-γ (IFN-γ). In this study we investigated the ability of the Th2-type cytokines interleukin (IL) -10, IL-6, and IL-4 to modulate IL-12 production in Mɸ/DC induced through the two pathways. IL-12 production was induced in Mɸ/DC from normal mice by stimulation with the combination of IFN-γ plus lipopolysaccharide (LPS) or Staphylococcus aureus Cowan I (a model for the T cell-independent pathway) or by co-culture with Chinese hamster ovary (CHO) cells transfected with the CD40L (a model for the T cell-dependent pathway). The effects of three Th2-type cytokines on IL-12 production by Mɸ/DC through the two pathways were examined. IL-10 inhibited IL-12 production induced through both pathways, although the inhibitory effect was more potent on the (IFN-γ + LPS)-induced pathway. IL-6 inhibited only (LPS + IFN-γ)-induced IL-12 production. The effect of IL-4 was particularly noteworthy: this cytokme inhibited (LPS + IFN-γ)-induced IL-12 production, whereas it potentiated the production of IL-12 induced by CD40L. Regulation of IL-12 protein production by IL-10 and IL-4 was found to correspond to the levels of mRNA accumulation for the p40 and p35 IL-12 genes, whereas the presence of IL-6 during stimulation decreased IL-12 protein production without affecting steady-state mRNA levels. These results indicate that IL-12 production in Mɸ/DC induced through a T cell-dependent or -independent pathway is positively or negatively regulated by particular cytokines at various control levels.
Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase
Authors: Welle Monika 
Published: January 2018

Abstract
Mast cells are one of the major effector cells in the pathogenesis of the immediate-type hypersensitivity reaction in a number of non-allergic immune disorders as well as in normal physiological processes. In addition, it has been shown recently that mast cells also play a significant role in a life-saving host response to bacterial reactions. But as much as the immunopathological role of mast cells has been acknowledged, these cells have also aroused much controversy and confusion. By now it is clear that one explanation for the sometimes even contradictory opinions on mast cell function arise from mast cell heterogeneity. This heterogeneity can express itself as differences in histochemical, biochemical, and functional characteristics. In vitro systems provided a powerful tool for the investigation of the basic mechanisms for mast cell development and differentiation and helped to demonstrate that mast cell heterogeneity can be traced back to certain cytokine patterns that are present in different microenvironments. In this context it has also been shown that the growth factors required for human mast cell differentiation are somewhat different than those for rodents. In rodents, the atypical, T cell-dependent mucosal type mast cell can be distinguished from the T cell-independent connective tissue-type mast cell. In humans, the strict classification into mucosal and connective tissue-type mast cells is not possible and the content of mast cell-specific proteases chymase and tryptase is the main criterion for mast cell subtypes in humans. The large quantities of tryptase and chymase that are synthesized by mast cells suggest and emphasize the significance of these proteinases in mast cell function and stimulate d investigations about the biological properties of these mast cell-specific proteases. Comparing their biological activities it becomes clear that they share some activities. On the other hand, tryptase seems to participate in proinflammatory mast cell function, whereas chymase seems to be more involved in inflammatory reactions. This review provides a short overview of the discovery, origin, development, and biological significance of mast cells and will then concentrate on mast cell heterogeneity in rodents and humans with respect to the mast cell proteases tryptase and chymase and their function.
Apoptosis in resolution of inflammation
Authors: Savill John 
Published: January 2018

Abstract
The last few years have seen the accumulation of compelling evidence that apoptosis (programmed cell death) plays a major role in promoting resolution of the acute inflammatory response. Neutrophils are constitutively programmed to undergo apoptosis, which limits their pro-inflammatory potential and leads to rapid, specific, and non-phlogistic recognition by macrophages and semi-professional phagocytes. Similar mechanisms have been implicated in clearance of eosinophils, lymphocytes, and monocytes and apoptosis also plays a role in remodeling the inflamed site by deletion of myofibroblasts. A growing understanding of the mechanisms regulating leukocyte apoptosis and of the molecules mediating safe phagocytic clearance of dying cells may yield new insights into the pathogenesis and therapy of inflammatory diseases.
Different cytokine profiles released by CD4+ and CD8+ tumor-draining lymph node cells involved in mediating tumor regression
Authors: Aruga Atsushi , Aruga Etsuko , Cameron Mark J , Chang Alfred E 
Published: January 2018

Abstract
We have previously demonstrated that the growth of weakly immunogenic murine sarcomas leads to the induction of immunologically specific preeffector cells in tumor-draining lymph nodes (TDLN). The in vitro activation of TDLN cells with anti-CD3 monoclonal antibodies (mAbs) and interleukin-2 (IL-2) resulted in the acquisition of effector function as measured by tumor regression in the adoptive immunotherapy of pulmonary metastases. Further studies were performed to characterize the mechanisms associated with in vivo tumor reactivity mediated by activated TDLN cells. By positive selection, CD4+ and CD8+ T cells were purified and activated by the anti-CD3/IL-2 method. CD8+, but not CD4+, cells manifested tumor-specific granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFN-γ) release in vitro, and elicited tumor regression in vivo. By contrast, only activated CD4+ were found to release significant amounts of IL-2 in response to tumor antigen but did not mediate tumor regression in vivo. Mixing the two purified populations enhanced the antitumor activity of the CD8+ T cells. In culture, IL-2 was found to augment the relative amount of tumor-specific release of GM-CSF and IFN-γ by activated TDLN cells. We found that the tumor-specific release of GM-CSF and IFN-γ by activated lymphocytes was strongly associated with the in vivo therapeutic efficacy of these cells. Evidence in support of this included the following: (1) cytokine release of TDLN derived after different durations of tumor growth correlated with tumor reactivity in adoptive transfer studies, (2) cytokine release of T cells derived from different lymphoid organs corresponded with tumor reactivity in adoptive transfer, and (3) in vivo administration of neutralizing mAb to IFN-γ and GM-CSF significantly inhibited the antitumor reactivity of TDLN cells. These studies document the contributory roles of IFN-γ, GM-CSF, and IL-2 released by activated CD4+ and CD8+ T cells involved in tumor regression.
IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium
Authors: Allavena P , Giardina G , Bianchi G , Mantovani A 
Published: January 2018

Abstract
Interleukin-15 (IL-15) is a recently described cytokine with IL-2-like stimulating activities on T lymphocytes and natural killer (NK) cells. IL-15 mediates its function through the β- and γ-chains of the IL-2 receptor. In this work, we have investigated the effect of IL-15 on the directional migration of NK cells in chemotaxis assays and on the ability of NK cells to bind to vascular endothelium. IL-15 (10–20 ng/mL) had chemotactic effects on freshly isolated resting NK cells as well as on long-termed IL-2-cultured NK cells. A checkerboard experiment demonstrated that migration in response to IL-15 was observed only in the presence of a positive gradient (chemotaxis). Overnight treatment of freshly isolated NK cells with IL-15 (10–20 ng/mL) augmented their binding to cultured endothelial cells (EC) in vitro, especially to resting EC. IL-15-activated NK cells bound to resting and tumor necrosis factor-activated EC by use of LFA-1/ICAM-1 and VLA-4/VCAM-1 adhesion pathways, essentially as untreated NK cells do. The fact that IL-15 increased NK cell binding to ICAM-1-transfected NIH-3T3 fibroblasts, together with the finding that IL-15 did not increase binding to extracellular matrix proteins, where the major molecules involved are VLA proteins, indicated that IL-15 primarily stimulates LFA-1-dependent adhesion. By increasing NK cell adhesion to vascular endothelium and migratory response, IL-15 is an important determinant of NK cell recruitment in tissues.
Increased mortality, blunted production of nitric oxide, and increased production of TNF-α in endotoxemic TGF-β1 transgenic mice
Authors: Vodovotz Yoram , Kopp Jeffrey B , Takeguchi Heather , Shrivastav Shashi , Coffin Deborah , Lucia M Scott , Mitchell James B , Webber Robert , Letterio John , Wink David , Roberts Anita B 
Published: January 2018

Abstract
The expression of the inducible isoform of nitric oxide synthase (NOS2, iNOS) is increased in patients undergoing sepsis as well as in animal models in which septic shock is induced by injection of bacterial lipopolysaccharide (LPS). Transforming growth factor-β1 (TGF-β1) potently suppresses NO production both in vitro and in vivo. After intraperitoneal injection of LPS, mice over-expressing a cDNA coding for active TGF-β1 in the liver (Alb/ TGF-β1) exhibited reduced serum levels of the NO reaction products NO2– + NO3– compared with controls. Paradoxically, while endotoxemic Alb/ TGF-β1 mice expressed much less NOS2 protein in peritoneal exudate cells than did endotoxemic wild-type mice, Alb/TGF-β1 mice expressed more NOS2 mRNA and protein in both liver and kidney. Alb/ TGF-β1 mice treated with LPS had eightfold higher serum tumor necrosis factor α (TNF-α) levels and experienced increased mortality compared with wild-type mice, which was associated with renal insufficiency. These results suggest that renal dysfunction, decreased production of NO, and/or increased production of TNF-α are associated with increased mortality of endotoxemic Alb/TGF-β1 mice.
G-CSF instillation into rat lungs mediates neutrophil recruitment, pulmonary edema, and hypoxia
Authors: Hierholzer Christian , Kelly Edward , Lyons Valerie , Roedling Eva , Davies Paul , Billiar Timothy R , Tweardy David J 
Published: January 2018

Abstract
Activated neutrophils (PMN) have been implicated in the pathogenesis of adult respiratory distress syndrome (ARDS). Granulocyte colony-stimulating factor (G-CSF) is essential for PMN production and activation of PMN functions. We have recently shown that levels of G-CSF mRNA in a rat model of hemorrhagic shock correlated with severity of shock, PMN infiltration, pulmonary edema, and hypoxia. To determine whether increased tissue levels of G-CSF contribute to PMN recruitment and PMN-mediated injury, we instilled G-CSF into the lungs by intratracheal injection. Animals treated with G-CSF became hypoxic, hypocapnic, and alkalotic and demonstrated increased BAL fluid cellularity compared with control animals. The wet-to-dry ratio increased significantly after G-CSF instillation and peaked at 12 h. Histological examination of the lungs from G-CSF-treated rats revealed marked edema and increased PMN within the interstitium and alveoli. These results indicate that the presence of G-CSF alone in the lung can lead to recruitment of PMN, lung injury, and impaired pulmonary function, suggesting that local production of G-CSF may contribute to the development of lung damage and possibly ARDS in the setting of resuscitated hemorrhagic shock.
Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity
Authors: Narayanan P K , Carter W O , Ganey P E , Roth R A , Voytik-Harbin S L , Robinson J P 
Published: January 2018

Abstract
We report evidence of a novel mechanism by which polychlorinated biphenyls might act as potent inducers of inflammation. Aroclor 1242 (A1242), a polychlorinated biphenyl mixture, and 2,2′,4,4′-tetrachlorobiphenyl (PCB47), a constituent of A1242 that produces the same patterns of effects, impaired the oxidative burst of human neutrophils by inhibiting the antioxidant enzyme superoxide dismutase, which converts O2–to H2O2. Pre-incubation of neutrophils with A1242 or PCB47 before stimulation with phorbol 12-myristate 13-acetate heightened the respiratory burst, producing a significant increase in intracellular O2- production along with a significant decrease in H2O2 production compared with unexposed agonist-stimulated neutrophils. This was also evident in a physiologically relevant situation in which neutrophils pre-incubated with A1242 were subsequently stimulated with a combination of N-formyl-L-methionyl-L-leucyl-L-phenylalanine and tumor necrosis factor-α. Incubation of bovine copper-zinc superoxide dismutase (EC 1.15.1.1) with A1242 or PCB47 in a cell-free system reversed the enzyme-mediated inhibition of 6-hydroxydopamine autoxidation, indicating that polychlorinated biphenyls inhibited superoxide dismutase activity. Low superoxide dismutase activity in neutrophils leads to imbalances between production of free radicals and antioxidant defense mechanisms, which can in turn induce tissue damage and hasten the onset of neutrophil apoptosis.
Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock
Authors: Essani Naeem A , Fisher Michael A , Simmons Carol A , Hoover Jennifer L , Farhood Anwar , Jaeschke Hartmut 
Published: January 2018

Abstract
We studied the role of P-selectin, an adhesion molecule known to be important for neutrophil localization to sites of inflammation, in a model of inflammatory liver injury. Male C3Heb/ FeJ (ET-sensitive) mice treated with 700 mg/kg galactosamine and 100 μg/kg Salmonella abortus equi endotoxin (Gal/ET), murine tumor necrosis factor α (TNF-α,15 μg/kg), or interleukin-1 (IL-1, 13–23 μg/kg), showed increased P-selectin mRNA levels in the liver. In contrast, C3H/HeJ (ET-resistant) mice responded only to cytokines with P-selectin mRNA formation. Whereas no P-selectin expression was detectable in control livers, there was temporary staining of endothelium in large blood vessels but not in sinusoids between 3 and 5 h after ET, TNF-α, or IL-1 treatment. Severe liver injury induced by Gal/ET at 7 h was not inhibited by an anti-P-selectin antibody in C3Heb/FeJ mice or in P-selectin-deficient animals. Sequestration of neutrophils in sinusoids, i.e. those neutrophils that have been identified as critical for the injury, was not affected by the antibody or in P-selectin-deficient mice. However, the temporary margination in portal and postsinusoidal venules was reduced by 75% in anti-P-selectin antibody-treated animals and by 51% in P-selectin-deficient mice. We conclude that hepatic P-selectin gene transcription in vivo involves cytokines. However, blocking P-selectin neither attenuated sinusoidal neutrophil sequestration nor prevented neutrophil-induced liver injury during endotoxin shock but attenuated neutrophil margination in larger vessels. Thus, our data demonstrate similarities and fundamental differences in the requirement for adhesion molecules to localize neutrophils in the liver vasculature compared to other organs during an inflammatory response.
Activated T lymphocytes induce degranulation and cytokine production by human mast cells following cell-to-cell contact
Authors: Bhattacharyya Siba P , Drucker llana , Reshef Tamar , Kirshenbaum Arnold S , Metcalfe Dean D , Mekori Yoseph A 
Published: January 2018

Abstract
Activated mast cells reside in close apposition to T cells in some inflammatory processes. In this study, we analyzed whether this close physical proximity affects human mast cell degranulation and cytokine release. Thus HMC-1 human mast cells or primary bone marrow-derived human mast cells were cocultured with activated and with resting T cells. Mast cells cocultured with activated T cells released histamine and β-hexosaminidase and produced tumor necrosis factor α (TNF-α), an effect that peaked at 20 h. Kinetics of histamine release paralleled the formation of heterotypic aggregates. Separation of the two cell populations with a porous membrane prevented mediator release and TNF-α production. Addition of the PI3-kinase inhibitor, wortmannin, inhibited the heterotypic adhesion-associated degranulation but not TNF-α production. These data thus indicate a novel pathway through which human mast cells are activated to both release granule-associated mediators and to produce cytokines in association with heterotypic adhesion to activated human T cells.