Journal of inflammation最新文献

{"title":"Proinflammatory responses are efficiently induced by homotrimeric but not heterotrimeric lymphotoxin ligands.","authors":"P S Hochman,&nbsp;G R Majeau,&nbsp;F Mackay,&nbsp;J L Browning","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The cytokine, lymphotoxin [LT, tumor necrosis factor beta (TNF beta)] is a potent mediator of proinflammatory and tumoricidal activities. Soluble lymphotoxin is a complex of three LT alpha chains. Its receptors, TNF-R55 and TNF-R75, bind in clefts formed by adjacent identical LT alpha monomers. LT also exists as membrane anchored heterotrimers comprised of LT alpha and LT beta chains. The major and minor membrane forms, LT alpha 1 beta 2 and LT alpha 2 beta 1, respectively, bind a unique receptor, LT beta-R. As LT alpha 2 beta 1 expresses an LT alpha-alpha cleft, it also binds TNF-R. In this report we have compared the effects of ligand engagement of TNF-R and LT beta-R by evaluating the ability of soluble LT alpha beta complexes to initiate activities of human umbilical vein endothelial cells which are characteristically signalled by TNF. We recently reported that soluble LT alpha 1 beta 2 signals via LT beta-R to mediate cytotoxicity of a subset of gamma interferon (IFN-gamma) treated carcinomas. We now show that human LT alpha beta heterotrimers do not efficiently activate LT beta-R+, TNF-R+ human endothelial cells in vitro and only inefficiently mediates lethal toxicity in mice. We also show that neither LT alpha beta heterotrimer signals via TNF-R; in fact LT alpha 2 beta 1 trimers fail to activate NF-kappa B and rather inhibit ligand-induced TNF-R signalling supporting the role for aggregation in TNF-R signalling. Thus, the ability of LT alpha beta complexes to efficiently initiate tumoricidal but not inflammatory activities distinguishes the LT/LT beta-R from the LT/TNF-R pathways and suggest novel strategies for exploiting the LT ligands in tumor therapy and for inhibiting TNF-R-mediated inflammatory sequellae.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"46 4","pages":"220-34"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19843480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor necrosis factor (TNF) receptors in cellular signaling of soluble and membrane-expressed TNF.","authors":"M Grell","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"47 1-2","pages":"8-17"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19877889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNF-induced intracellular signaling leading to gene induction or to cytotoxicity by necrosis or by apoptosis.","authors":"W Fiers,&nbsp;R Beyaert,&nbsp;E Boone,&nbsp;S Cornelis,&nbsp;W Declercq,&nbsp;E Decoster,&nbsp;G Denecker,&nbsp;B Depuydt,&nbsp;D De Valck,&nbsp;G De Wilde,&nbsp;V Goossens,&nbsp;J Grooten,&nbsp;G Haegeman,&nbsp;K Heyninck,&nbsp;L Penning,&nbsp;S Plaisance,&nbsp;K Vancompernolle,&nbsp;W Van Criekinge,&nbsp;P Vandenabeele,&nbsp;W Vanden Berghe,&nbsp;M Van de Craen,&nbsp;V Vandevoorde,&nbsp;D Vercammen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>TNF-induced apoptosis, e.g. in murine PC60 cells, requires the TNF receptor p55 (TNF-R55) and the TNF receptor p75 (TNF-R75); the latter even does not have to be triggered. The intracellular domain of TNF-R55 can be activated in the cytosol by linking it to the trimeric CAT protein; induction of this fusion protein leads to a full TNF response. A new MAP kinase, p38, has been shown to be also activated by TNF. This activation is essential for gene induction, but not for cytotoxicity in L929 cells. TNF treatment of L929 leads to reactive oxygen formation in the mitochondria, resulting in cell death by necrosis. TNF treatment of many other cell types results in apoptosis, and this process involves activation of one or more ICE homologs (IHO). In the mouse, seven cysteine proteases of the IHO family have been cloned and partially characterized. One or more of these IHOs is involved in cell killing by proteolysis of critical substrate(s). One substrate, which may be a key effector molecule in the apoptotic process, is PITSLRE kinase.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"47 1-2","pages":"67-75"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19878942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity.","authors":"M E Blazka,&nbsp;D R Germolec,&nbsp;P Simeonova,&nbsp;A Bruccoleri,&nbsp;K R Pennypacker,&nbsp;M I Luster","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Nuclear transcription factors, such as NF-kB and NF-IL6, are believed to play an important role in regulating the expression of genes that encode for products involved in tissue damage and inflammation and, thus, may represent early biomarkers for chemical toxicities. In the present study changes in DNA binding activity of these factors were examined in livers of mice administered hepatotoxic doses of acetaminophen (APAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatotoxic doses of APAP, their binding activities were transiently lost and is in contrast to AP-1 transcription factor where activation occurs under similar conditions. These changes corresponded with increased release of inflammatory mediators (IL-6, serum amyloid A) and increased levels of enzymatic markers of hepatocyte damage. Similarly, treatment of mice with gadolinium chloride, an inhibitor of Kupffer cell activation and known to protect against APAP-induced hepatotoxicity, reduced the observed pathophysiological response in the liver while altering the APAP-associated changes in NF-kB DNA binding activity. NF-kB was found predominantly in parenchymal and endothelial cells and was composed primarily of relatively inactive p50 homodimer subunits in control liver. Taken together, these studies suggest that hepatotoxicity is associated with early and complex changes in DNA binding activities of specific transcription factors. In particular, NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators and is analogous to that previously observed in certain other cell systems such as B lymphocytes.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"47 3","pages":"138-50"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20066035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crescentic glomerulonephritis in interferon-gamma receptor deficient mice.","authors":"C Haas, B Ryffel, M Le Hir","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Activation of macrophages by T cells is considered an initiating event in glomerular crescent formation. Since interferon-gamma (INF gamma) is a key mediator in T-cell-mediated activation of macrophages, we decided to test its role in a model of crescentic glomerulonephritis. An anti-glomerular basement membrane (GBM) serum was injected intravenously in presensitized wild-type or IFN gamma receptor deficient (IFN gamma(R)-/-) mice. Glomerulonephritis with glomerular crescents and tubulointerstitial inflammation developed in both strains, even though most evaluated morphological parameters and proteinuria indicated a less severe pathology in the mutant mice compared to the wild type. Thus, IFN gamma is not essential either for glomerular crescent formation or for tubulointerstitial involvement in anti-GBM glomerulonephritis in mice. In conclusion, the role of macrophages in this model might have been overestimated, or other cytokines may compensate for deficient IFN gamma signaling in the activation of macrophages.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"47 4","pages":"206-13"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of TNF/TNF receptor and of Fas ligand to toxicity in murine models of endotoxemia and bacterial peritonitis.","authors":"D Heumann,&nbsp;D Le Roy,&nbsp;G Zanetti,&nbsp;H P Eugster,&nbsp;B Ryffel,&nbsp;M Hahne,&nbsp;J Tschopp,&nbsp;M P Glauser","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Fas/Fas ligand and TNF/TNF receptors are involved in apoptosis. Whether both systems are involved in septic shock has not been determined so far. We investigated the role of TNF/TNFR and Fas/Fas ligand in models of endotoxemia and of speticemia in mice. Upon LPS challenge, TNF and TNFR p55 were involved in the process inducing lethality. FasL did not contribute to enhance lethality, as evidenced in gld mice, lacing FasL. Following an intraperitoneal injection of live E. coli, TNF and TNFR p55 were necessary to combat infection. Disruption of either gene was associated with enhanced lethality and failure to clear the bacteria. No effect observed in gld mice in this peritonitis model. Thus, these observations confirmed the pathogenic role of TNF/TNFR in endotoxemia and its beneficial role in local bacterial infections. In addition the data ruled out a major role for Fas/FasL in septic shock in mice.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"47 4","pages":"173-9"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Superantigen-induced transcriptional activation of the human TNF gene promoter in T cells.","authors":"B Krämer,&nbsp;T Machleidt,&nbsp;K Wiegmann,&nbsp;M Krönke","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Superantigens, such as staphylococcal enterotoxins (SE), cause food poisoning and shock, which is mediated at least in part by TNF. We have examined the mechanism of superantigen-induced activation of the TNF gene promoter in primary human peripheral blood T lymphocytes and in the leukemic T cell line Jurkat. Like stimulation of the T cell receptor complex through CD3 ligation, SEB induces binding of nuclear proteins to Egr- and Jun/ATF-related consensus sequences present between nucleotides -170 and -100 of the TNF promoter 5' flanking region. By cotransfection of Jurkat T cells with constructs containing TNF promoter deletion mutants linked to a CAT reporter gene, it is shown that superantigens can activate transcription from these two adjacent ETs and Jun/ATF binding elements. Superantigen-induced binding of Egr-1 and Jun/ATF is markedly reduced by okadaic acid, suggesting that phosphatases are involved in the signaling of SE. When compared to CD3 ligation, superantigens activate the TNF promoter more potently, which is likely due to costimulatory signals provided by superantigen presenting cells.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"45 3","pages":"183-92"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19577606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant endotoxin-binding protein (rBPI23) attenuates endotoxin-induced circulatory changes in humans.","authors":"R J de Winter,&nbsp;M A von der Möhlen,&nbsp;H van Lieshout,&nbsp;N Wedel,&nbsp;B Nelson,&nbsp;N Friedmann,&nbsp;B J Delemarre,&nbsp;S J van Deventer","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>In the present study the protective effect of a recombinant endotoxin-binding protein rBPI23 on the circulatory changes in experimental endotoxemia in humans was investigated. In a controlled, blinded crossover study, eight volunteers were challenged twice with an intravenous bolus injection of endotoxin (40 EU/kg body weight), and concurrently received either rBPI23 (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg). Hemodynamic parameters were obtained non-invasively by means of M-mode, two-dimensional, and Doppler echocardiography. rBPI23 significantly reduced indices of the endotoxin-induced hyperdynamic circulation. rBPI23 treatment significantly reduced increase in cardiac index (P = 0.0156). rBPI23 treatment diminished the endotoxin-induced decrease in systemic vascular resistance index (P = 0.0304). rBPI23 did not prevent the endotoxin-induced rise in body temperature and systolic, diastolic and mean arterial pressure were not significantly different in the rBPI23- and placebo-treatment arm. Both treatment periods showed a small reduction in end diastolic and end systolic volumes. rBPI23 treatment slightly reduced the increase in M-mode ejection fraction and fractional shortening. These results indicate that rBPI23 is capable of attenuating the potentially deleterious circulatory effects of endotoxin in humans.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"45 3","pages":"193-206"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19577608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation.","authors":"B M Brinkman,&nbsp;D Zuijdeest,&nbsp;E L Kaijzel,&nbsp;F C Breedveld,&nbsp;C L Verweij","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Tumor necrosis factor alpha (TNF alpha) is a central mediator of the immunological response and the location of the gene within the major histocompatibility complex (MHC) has prompted much speculation about the role of TNF alpha alleles in inflammatory and MHC-associated autoimmune diseases. A G to A transition polymorphism at position -308 of the TNF alpha promoter/enhancer region has been described. The uncommon -308A allele was shown to be strongly associated with human leukocyte antigen (HLA)-DR3, known to be related to a TNF alpha \"high producer\" phenotype. In support for a clinical relevance, the -308A allele is implicated in susceptibility for cerebral malaria. In this study, we determined the junctional consequences of the TNF -308 polymorphism. Therefore, we analyzed both allelic forms (TNF alpha(-308G) and TNF alpha(-3O8A)) of the TNF alpha enhancer/promoter region (-598/+108) in a transient transfection system, using chloramphenicol acetyltransferase (CAT) as reporter gene. The T cell line Jurkat and the B cell line Raji served as hosts in these experiments. The results showed no differences in the level of inducible reporter gene expression between the TNF(-3O8G)/CAT and the TNF(-308A)/CAT constructs. These data were confirmed by allele specific TNF alpha transcript quantification (ASTQ) analysis, which demonstrated that both TNF alleles contribute equally to the total amount of mRNA in peripheral blood mononuclear cells (PBMCs) stimulated with phorbol 12-myristate 13-acetate (PMA)/anti-CD3. In analogy, no difference between the level of transcription of the -308A and -308G alleles was observed in lipopolysaccharide (LPS)-stimulated peripheral blood monocytes. This study indicates that the TNF alpha -308 G to A transition is not responsible for differential TNF alpha production induced by standard in vitro stimuli.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"46 1","pages":"32-41"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19800432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations.","authors":"K Zwingenberger,&nbsp;S Wnendt","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Three decades of immunological investigations using thalidomide are reviewed. Both in vitro and in vivo investigations are in accordance with the clinical finding that thalidomide does not impede T-cell competence in the control of infection by mycobacteriae. The term immunosuppressant does not apply. The immunomodulatory effects of thalidomide are evident in a myriad of phenomenological changes, and a molecularly defined common denominator of these activities is not known at present. Critical assessment with the objective to account for the clinical activity of thalidomide in specific human diseases leads to a focus on effects of thalidomide on phagocytic leukocytes and endothelia. The former are responsive to thalidomide by modulation of cytokine synthesis in vitro and in vivo; this activity can be shown using monocyte-specific stimuli in peripheral blood mononuclear cells but also in other phagocytic cells like microglia. For technical reasons, endothelial cells have until now been tested primarily in vitro. However, there is solid evidence now from intravital microscopy that the induction of adhesivity in postcapillary venules by LPS is modulated by thalidomide. Altered surface antigen expression has been described on leukocytes obtained from humans and experimental animals treated with thalidomide, but convincing evidence is lacking for in vitro modulation of surface antigen expression on leukocytes (as opposed to the modulation of adhesion antigens on endothelial cells stimulated by LPS or exogenous TNF alpha in the presence of thalidomide). Therefore, in vivo redistribution is likely to account for some, if not all, changes in circulating leukocyte phenotypes. The immunopathological conditions most clearly responsive to thalidomide are vasculitic alterations of post-capillary venules either in the context of mycobacterial infection (in the case of erythema nodosum leprosum) or mucocutaneous aphths. In both instances (as in the majority of focal inflammatory lesions), leukocyte infiltration and cytokine responses, in particular TNF alpha, are present. Thalidomide acts clinically not only by palliation of existing lesions but also by prevention of recurrence. The mechanism operates in skin, mucosa and parts of the nervous system and is most readily explained by synergism of TNF alpha modulation and a separate point of action on leukocyte migration patterns.</p>","PeriodicalId":79405,"journal":{"name":"Journal of inflammation","volume":"46 4","pages":"177-211"},"PeriodicalIF":0.0,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19843478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}