European Journal of Immunology
0014-2980
1521-4141
Đức
Cơ quản chủ quản: Wiley-VCH Verlag , WILEY
Lĩnh vực:
Immunology and AllergyImmunology
Các bài báo tiêu biểu
Interleukin 2 mRNA induction in human lymphocytes: analysis of the synergistic effect of a calcium ionophore A23187 and a phorbol ester Abstract Induction of interleukin 2 (IL2) mRNA in human tonsillar lymphocytes under various conditions was examined by cytoplasmic dot hybridization using a 32 P‐labeled IL 2 cDNA probe to study the signal transduction mechanisms which lead to IL2 gene expression. A tumor‐promoting phorbol ester, 12‐O‐tetradecanoyl‐phorbol 13‐ace‐tate (TPA), acted synergistically with a Ca2+ ionophore A23187 or phytohemaggluti‐nin (PHA) to induce a high level of IL2 mRNA in lymphocytes, whereas each of them by itself could not induce the mRNA production. In two‐step culture experiments the lymphocytes pulse‐incubated with TPA for 1 h (the first culture) could efficiently initiate IL2 mRNA production by subsequent culture with A23187 or PHA (the second culture). Results obtained by removal of extracellular Ca2+ from either the first or second culture revealed that Ca2+ was not necessarily required during the first culture with TPA, but it is essential in the second culture with A23187 or PHA, regardless of the presence or absence of Ca2+ in the first culture. A reagent known to be a calmodulin antagonist, N‐(6‐aminohexyl)‐5‐chloro‐l‐naphthalenesulfonamide (W‐7), almost completely inhibited the IL2 mRNA induction in A23187‐TPA‐stimu‐lated lymphocytes at a concentration of 25 μM, whereas N‐(6‐aminohexyl)‐l‐naph‐thalenesulfonamide that has much lower affinity for calmodulin than W‐7 did not inhibit at this concentration. The IL2 mRNA induction was also blocked by the addition of 50 UM of 8‐(N, N‐diethylamino)‐octyl‐3,4,5‐trimethoxybenzoate hydro‐ chloride which is known to block the release of Ca2+ from intracellular storage sites. These results show that mobilization of Ca2+ and the calmodulin‐dependent regulatory system appear to work synergistically with TPA which probably activates protein kinase C in the pathway to IL2 gene expression.
Tập 15 Số 12 - Trang 1204-1208 - 1985
Mini‐review: The nuclear protein HMGB1 as a proinflammatory mediator Abstract The intranuclear architectural protein that is termed high mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator when present extracellularly. HMGB1 has been demonstrated to be a long‐searched‐for nuclear danger signal passively released by necrotic, as opposed to apoptotic, cells that will induce inflammation. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes in a process requiring acetylation of the molecule, which enables translocation from the nucleus to secretory lysosomes. Subsequenttransport out of the cells depends on a secretion signal mediated by either extracellular lysophophatidyl‐choline or ATP. HMGB1 passively released from necrotic cells and HMGB1 actively secreted byinflammatory cells are thus molecularly different. Extracellular HMGB1 acts as a cytokine by signaling via the receptor for advanced glycated end‐products and via members of the Toll‐like receptor family. The initiated inflammatory responses include the production of multiple cytokines, chemoattraction of certain stem cells, induction of vascular adhesion molecules and impaired function of intestinalepithelial cells. Therapeutic administration of HMGB1 antagonists rescues mice from lethal sepsis, even when initial treatment is delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
Tập 34 Số 6 - Trang 1503-1512 - 2004
Reprogramming mitochondrial metabolism in macrophages as an anti‐inflammatory signal Mitochondria are master regulators of metabolism. Mitochondria generate ATP by oxidative phosphorylation using pyruvate (derived from glucose and glycolysis) and fatty acids (FAs), both of which are oxidized in the Krebs cycle, as fuel sources. Mitochondria are also an important source of reactive oxygen species (ROS), creating oxidative stress in various contexts, including in the response to bacterial infection. Recently, complex changes in mitochondrial metabolism have been characterized in mouse macrophages in response to varying stimuli in vitro. In LPS and IFN‐γ‐activated macrophages (M1 macrophages), there is decreased respiration and a broken Krebs cycle, leading to accumulation of succinate and citrate, which act as signals to alter immune function. In IL‐4‐activated macrophages (M2 macrophages), the Krebs cycle and oxidative phosphorylation are intact and fatty acid oxidation (FAO) is also utilized. These metabolic alterations in response to the nature of the stimulus are proving to be determinants of the effector functions of M1 and M2 macrophages. Furthermore, reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Here, we describe the role that metabolism plays in macrophage function in infection and immunity, and propose that reprogramming with metabolic inhibitors might be a novel therapeutic approach for the treatment of inflammatory diseases.
Tập 46 Số 1 - Trang 13-21 - 2016
Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS‐independent activation of NF‐κB Abstract Reactive oxygen species (ROS) generated by the cellular NADPH‐oxidase are crucial for phagocytic killing of ingested microbes and have been implicated as signaling molecules in various processes. For example, ROS are thought to be involved in activation of the transcription factor NF‐κB, central for mediating production of proinflammatory cytokines in response to inflammatory stimuli. Several studies have demonstrated that inhibitors of the NADPH‐oxidase interfere with NF‐κB activation and production of proinflammatory cytokines. Curiously, patients with chronic granulomatous disease (CGD), an immunodeficiency characterized by an inability to produce ROS, are not only predisposed to severe infections, but also frequently develop various inflammatory complications indicative of exaggerated inflammatory responses. Here, we show that human CGD leukocytes display a hyperinflammatory phenotype with increased production of proinflammatory cytokines in response to stimulation with Toll‐like receptor agonists. The hyperinflammatory phenotype was also evident in mononuclear cells from CGD mice (gp91phox – / – ), but not in control cells in the presence of NADPH‐oxidase inhibitor diphenyleneiodonium, probably reflecting NADPH‐oxidase‐independent effects of the inhibitor. Furthermore, we show that the major steps involved in NF‐κB activation were intact in human CGD cells. These data indicate that ROS were nonessential for activation of NF‐κB and their production may even attenuate inflammation.
Tập 37 Số 4 - Trang 1087-1096 - 2007
Electrochemical reduction of immunoglobulins specific reduction of the inter‐heavy chain disulfide bridges of igg Abstract Electrochemical reduction of IgG disulfide bridges has been studied and the number of disulfide bridges reduced determined by several methods: coulometry and polarographic titrations at the mercury electrode with electroactive alkylating agents, such as iodoacetamide and N‐ethylmaleimide. The three methods give identical results. Determination and localization of reduced disulfide bridges examined in the four IgG subclasses show that the reduction occurs exclusively on the interheavy chain disulfide bridges.
Tập 3 Số 9 - Trang 537-542 - 1973
IL‐3 synergises with basophil‐derived IL‐4 and IL‐13 to promote the alternative activation of human monocytes Basophil‐derived IL‐4 is involved in the alternative activation of mouse monocytes, as recently shown in vivo. Whether this applies to human basophils and monocytes has not been established yet. Here, we sought to characterise the interaction between basophils and monocytes and identify the molecular determinants. A basophil‐monocyte co‐culture model revealed that IL‐3 and basophil‐derived IL‐4 and IL‐13 induced monocyte production of CCL17, a marker of alternative activation. Critically, IL‐3 and IL‐4 acted directly on monocytes to induce CCL17 production through histone H3 acetylation, but did not increase the recruitment of STAT5 or STAT6. Although freshly isolated monocytes did not express the IL‐3 receptor α chain (CD123), and did not respond to IL‐3 (as assessed by STAT5 phosphorylation), the overnight incubation with IL‐4 (especially if associated with IL‐3) upregulated CD123 expression. IL‐3‐activated JAK2‐STAT5 pathway inhibitors reduced the CCL17 production in response to IL‐3 and IL‐4, but not to IL‐4 alone. Interestingly, monocytes isolated from allergen‐sensitised asthmatic patients exhibited a higher expression of CD123. Taken together, our data show that the JAK2‐STAT5 pathway modulates both basophil and monocyte effector responses. The coordinated activation of STAT5 and STAT6 may have a major impact on monocyte alternative activation in vitro and in vivo.
Tập 45 Số 7 - Trang 2042-2051 - 2015
Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients Abstract Hepatitis C virus (HCV) readily establishes high‐level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV‐specific CD8+ CTL to clear viral replication. Virus‐induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus‐specific CD8+ CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection. Flow cytometric analysis of purified resting peripheral NK cells showed no evidence of NK cell activation, while analysis of natural cytotoxicity receptors (NCR) showed that NK cells from HCV‐infected patients had selective increased expression of NKp30 and NKp46. NK cells had corresponding conserved cytotoxic activity against all targets with the exception of HepG2 hepatoma cells. Freshly separated NK cells from HCV patients showed significant production of IL‐10 and normal concentrations of IFN‐γ upon cell‐mediated triggering. Thus, increased expression of NKp30 during HCV infection with increased IL‐10 production could contribute, once NK cells localize in the liver, to a NK‐DC crosstalk leading to skewing of subsequent adaptive immune responses and lack of virus control.
Tập 37 Số 2 - Trang 445-455 - 2007
Polyclonal effect of HgCl<sub>2</sub> in the rat, its possible role in an experimental autoimmune disease Abstract Mercuric chloride induces an immune glomerulonephritis in Brown‐Norway (BN) but not in Lewis (LEW) rats. Injection of HgCl2 into BN rats regularly produced a transient appearance of plaque‐forming cells (PFC) of anti‐2,4,6‐trinitrophenyl and anti‐sheep red blood cell specificity and circulating anti‐single‐stranded DNA antibodies. Addition of HgCl2 to spleen cell cultures from BN rats induced an increase in anti‐trinitrophenyl PFC and reverse PFC. This effect was no longer observed when nylon wool column‐depleted or anti‐Thy‐1 antiserum‐treated spleen cells were cultured in the presence of HgCl2 . These data suggest that HgCl2 acts as a polyclonal activator on spleen cells in BN rats, but not on isolated B lymphocytes. In contrast, no effect of HgCl2 on immunoglobulin production was observed in LEW rats. Since polyclonal activation and immune‐type nephritis are both seen in BN but not in LEW rats, polyclonal activation may participate in the pathogenesis of the HgCl2 ‐induced autoimmune disease of BN rats.
Tập 12 Số 7 - Trang 620-625 - 1982
Three classes and four (sub)classes of rat immunoglobulins: IgM, IgA, Ige and IgG<sub>1</sub>, IgG<sub>2a</sub>, IgG<sub>2b</sub>, IgG<sub>2c</sub> Abstract Class or subsclass‐specific differences have been investigated in the monoclonal immunoglobulins produced by 184 secreting immunocytomas raised in the LOU/Wsl inbred strain of rats. Seven classes or subclasses of rat immunoglobulins were detected and the names IgM, IgA, IgE, IgG1 , IgG2a , IgG2b and IgG2c proposed for them. The sedimentation coefficients of rat IgG1 , IgG2a and IgG2c were found to be respectively, 6.7, 6.4 and 6.7 S. Rat IgG1 , IgG2a and IgG2c were found to cross‐react with antisera to human γ‐chains.
Tập 4 Số 1 - Trang 44-48 - 1974
F4/80, a monoclonal antibody directed specifically against the mouse macrophage Abstract A hybridoma clone which secretes a macrophage (MΦ)‐specific monoclonal antibody, F4/80, was produced by fusing spleen cells from a rat hyperimmunized with cultured thioglycollate‐induced mouse peritoneal MΦ with a mouse myeloma, NS1. Binding of antibody to primary cells and cell lines was detected by radioimmune indirect binding assay, autoradiography or fluorescence‐activated cell sorter analysis. F4/80 binds to mouse MΦ from the peritoneal cavity or other sources, blood monocytes, MΦ derived from bone marrow precursors in culture and MΦ‐like cell lines, but not to other cells, including polymorphonuclear leukocytes, lymphocytes or fibroblasts. F4/80 does not bind to MΦ via Fc receptors, is not cytotoxic and is of the rat IgG2b subclass. Since F4/80 binds to all MΦ defined by adherence, morphology and immune phagocytosis, it provides a new marker to define the MΦ in the mouse. Large differences in expression of antigen F4/80 were found, depending on intraperitoneal stimulation, time in culture and stage of maturation. Immunoprecipitation experiments demonstrated that the antigen F4/80 is part of a component of Mr 160000 which is synthesized by the MΦ and, at least in part, exposed on the cell surface.
Tập 11 Số 10 - Trang 805-815 - 1981