Oxidative stress and gene expression: the AP-1 and NF-kappaB connections.
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Gene Expression↗
Biomedical subjects
F Guido
Publications and source records attributed to F Guido.
Mitogen-activated kinase kinase kinase 1 regulates T cell receptor- and CD28-mediated signaling events which lead to NF-kappaB activation.
Optimal activation of Rel/NF-kappaB transcription factors in T lymphocytes requires a CD28-delivered co-stimulatory signal in addition to TCR engagement. Although, Rel/NF-kappaB transcription factors are critical regulators of many T cell functions, the mechanisms and molecules, which link the surface receptors to their activation, are poorly characterized. Using Jurkat T cells stimulated with superantigen presented on B7-positive APC, we showed that CD28- and TCR-stimulated NF-kappaB-dependent transcription is associated to the activation of IkappaB kinase beta (IKKbeta) and, to a lesser extent, of IkappaB kinase alpha (IKKalpha). A dominant negative mutant of the MAP3 kinase MEKK1, a kinase known to regulate the JNK pathway and to activate NF-kappaB-dependent transcription in many cell types, strongly inhibits CD28- and TCR-induced IKK activity, whereas the dominant negative mutants of the NF-kappaB-inducing kinase (NIK) did not exert any significant effects. In addition, TCR/CD28 stimulation results in the recruitment and autophosphorylation of endogenous MEKK1, whereas endogenous NIK was not detectably activated. Our data identify MEKK1 as a critical step in coupling signals initiated by TCR and CD28 to the downstream pathways which lead to both AP-1 and NF-kappaB activation in T lymphocytes.
B7-1 Antigen↗
Increased levels of lactoferrin in synovial fluid but not in serum from patients with rheumatoid arthritis.
Lactoferrin is a multifunctional immunoregulatory protein, stored in specific granules of neutrophil granulocytes, from which it is released following cell activation. As activated neutrophils play a crucial role in the destruction of synovial joints in rheumatoid arthritis, we evaluated lactoferrin concentration in synovial fluid and sera from 21 patients with rheumatoid arthritis and 11 patients with osteoarthritis. We also measured lactoferrin levels in sera from 12 healthy controls. Lactoferrin was measured by a solid-phase inhibition immunoassay. Median lactoferrin levels were significantly higher in synovial fluid from rheumatoid arthritis than from osteoarthritis patients (P = 0.0002). In contrast, no significant difference was found between serum lactoferrin from patients with rheumatoid arthritis or osteoarthritis compared with normal controls. In patients with rheumatoid arthritis, lactoferrin concentrations were higher in synovial fluid than in sera (P = 0.036). In both rheumatoid arthritis and osteoarthritis no correlation was found between serum and synovial fluid lactoferrin (P = 0.51 and P = 0.5, respectively). In synovial fluid from patients with rheumatoid arthritis, lactoferrin concentrations correlated with neutrophil granulocyte count (P < 0.0001), but neither serum nor synovial lactoferrin levels correlated with disease activity (P = 0.32 and P = 0.25, respectively). In conclusion, lactoferrin is a reliable marker of neutrophil activation at sites of inflammation in rheumatoid synovitis, but does not represent a marker of disease activity.
Adult↗
Nuclear factor kB-independent cytoprotective pathways originating at tumor necrosis factor receptor-associated factor 2.
Most normal and neoplastic cell types are resistant to tumor necrosis factor (TNF) cytotoxicity unless cotreated with protein or RNA synthesis inhibitors, such as cycloheximide and actinomycin D. Cellular resistance to TNF requires TNF receptor-associated factor 2 (TRAF2), which has been hypothesized to act mainly by mediating activation of the transcription factors nuclear factor kB (NFkB) and activator protein 1 (AP1). NFkB was proposed to switch on transcription of yet unidentified anti-apoptotic genes. To test the possible existence of NFkB-independent cytoprotective pathways, we systematically compared selective trans-dominant inhibitors of the NFkB pathway with inhibitors of TRAF2 signaling for their effect on TNF cytotoxicity. Blockade of TRAF2 function(s) by signaling-deficient oligomerization partners or by molecules affecting TRAF2 recruitment to the TNF receptor 1 complex completely abrogated the cytoprotective response. Conversely, sensitization to TNF cytotoxicity induced by a selective NFkB blockade affected only a fraction of TNF-treated cells in an apparently stochastic manner. No cytoprotective role for c-Jun amino-terminal kinases/stress-activated protein kinases (JNKs/SAPKs), which are activated by TRAF2 and contribute to stimulation of activator protein 1 activity, could be demonstrated in the cellular systems tested. Although required for cytoprotection, TRAF2 is not sufficient to protect cells from TNF + cycloheximide cytotoxicity when overexpressed in transfected cells, thus indicating an essential role of additional TNF receptor 1 complex components in the cytoprotective response. Our results indicate that TNF-induced cytoprotection is a complex function requiring the integration of multiple signal transduction pathways.
Animals↗
Apoptotic, non-apoptotic, and anti-apoptotic pathways of tumor necrosis factor signalling.
Early events in the signalling of tumor necrosis factor-receptor 1 (TNF-R1), which is the main TNF receptor on most cell types, have been clarified recently. A multimolecular signal transducing complex from which several pathways originate rapidly forms upon TNF-induced aggregation of the receptor. Although fully capable of transducing apoptotic signals, which depend on the adapter Fas-associated death domain protein (FADD) and on the subsequent recruitment/activation of the apoptotic proteases, TNF-R1 usually does not kill cells; this is due to the induction of a complex cytoprotective response that requires TNF-receptor associated factor 2 (TRAF2), a signal transducer that couples TNF-R1 to both nuclear factor kappaB (NFkappaB)-dependent and NFkappaB-independent transcriptional events implicated in induction of genes protecting from TNF cytotoxicity. Although absolutely required for cytoprotection, TNF-receptor associated factor 2 is not sufficient to protect cells from TNF, thus suggesting that it may act in concert with additional TNF-R1 complex components. In this commentary, we will discuss some critical aspects of TNF-R1 signal transduction that are not fully understood: Why do cells not die before the protective protein synthesis has occurred? What are the mechanisms implicated in the termination of each TNF-R1-elicited response? Are there regulatory mechanisms capable of influencing the composition of the TNF-R1 complex and, consequently, the propagation of specific signals?
Animals↗
Effectiveness of a home-made meat based formula (the Rezza-Cardi diet) as a diagnostic tool in children with food-induced atopic dermatitis.
The aim of this study was to investigate the effectiveness of a home-made meat based formula (the Rezza-Cardi diet), as a diagnostic tool for children with atopic dermatitis and suspected multiple food hypersensitivity. Severity scores for atopic dermatitis, body weight and serum lipid profile were evaluated at baseline and four weeks following the feeding with the home-made meat based formula in 16 children with atopic dermatitis and suspected multiple food hypersensitivity. The severity score of the skin lesions improved considerably in all the children; no significant difference was observed in the serum lipid levels before and after one month following the feeding with the home-made meat based formula. All children gained weight according to the Italian Standards. The results of this study indicate that the home-made meat based formula is a useful elimination diet in children with atopic dermatitis and suspected multiple food hypersensitivity.
Child, Preschool↗
Crossed renal ectopia with fusion.
The case of three-year old girl with right to left crossed renal ectopia with fusion is described. This malformation presented only microhematuria and urinary tract infections. The diagnosis was established by means of biochemical and radiographic investigations.
Child, Preschool↗
[Nailfold capillaroscopy in normal children between 0 and 16 years of age].
BACKGROUND: Nailfold capillaroscopy is a technique used in childhood and adults for morpho-functional study of peripheral microcirculation. The aim of the present study is to evaluate the evolution of the microcirculation. METHODS: Nailfold capillaroscopy was performed in eighty-six healthy children (48 boys and 38 girls) aged 5 months to 16 years. All the subjects were divided into 5 groups for age. RESULTS: A progressive morphological and dynamic development of peripheral microcirculation in the early years of life was observed. CONCLUSIONS: Therefore, nailfold capillaroscopy is a simple, noninvasive, easily repetitive method which allows to observe the physiological development and a possible pathology of naifold capillaries.
Child↗
Two spatially distant epitopes of human lactoferrin.
Lactoferrin (LF) is an iron binding protein, which may represent a target for antineutrophil cytoplasmic antibodies (ANCA) in patients affected by rheumatoid arthritis, ulcerative colitis, and primary sclerosing cholangitis. Here we describe the production and characterization of two new monoclonal antibodies (MAbs) against human LF. These MAbs (AGM 10.14, an IgG1, and AGM 2.29, an IgG2b) recognize spatially distant epitopes of LF as assessed by cross-blocking experiments. We also demonstrated by indirect immunofluorescence that both MAbs react with ethanol-fixed neutrophil granulocytes showing a perinuclear staining pattern. AGM 2.29 and AGM 10.14 have been utilized as capture and labeled tracer antibody, respectively, in a double determinant immunoassay (DDIA) to measure soluble LF. The results obtained show that this DDIA allows us to quantify even low concentrations of LF, the maximal range of the assay sensitivity being between 12 and 780 ng/ml. Therefore, AGM 10.14 and AGM 2.29 may represent useful reagents for studying the role of autoantibodies to LF as well as for measuring soluble LF, which is a reliable secretory marker of neutrophil activation.
Animals↗
[Lymphocytes and renal damage].
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B-Lymphocytes↗
[Cytokines and renal injury].
Cytokines play an important role in most physiological and pathological processes. In this note the authors review recent literature data about cytokines in mediating renal inflammatory diseases. These molecules are involved in every phase of inflammatory injury induce expression of MHC class II and adhesion molecules on renal cells, synthesis of chemoattractants; they are also involved in leukocyte localization and play a role in the induction of cell proliferation and the accumulation of extracellular matrix. The disturbances of the cytokine network may lead to inflammatory kidney disease that could be treated by novel therapeutic agents like anticytokine antibodies.
Animals↗
[Evaluation of N-acetyl-beta glucosaminidase in upper and lower urinary tract infections in childhood. Clinical study of 168 children].
BACKGROUND: Urinary N-acetyl-beta-glucosaminidase (NAG) is a renal tubular enzyme that may be used as a marker of tubular damage. METHODS: We studied 96 patients 1 to 8 years old and considered NAG excretion to distinguish cystitis from pyelonephritis. Whenever urinary NAG values were expressed in relation to urinary creatinine concentration and compared with urinary NAG values in 72 normal controls 1 to 14 years old grouped by age. RESULTS: Our results demonstrate that urinary NAG levels are elevated in children with pyelonephritis in the presence or absence of urinary tract abnormality. CONCLUSIONS: Therefore, we conclude that NAG may be considered as a further criteria in the diagnosis of upper urinary tract infection and interstitial tubular damage.
Acetylglucosaminidase↗
[Crossed renal ectopy with fusion. Report of a case].
Crossed renal ectopia is a rare urinary tract anomaly, often associated with malformations involving various organs and systems. We report a case of crossed renal ectopy with fusion, without associated abnormalities. Recurrent abdominal pain, sometimes with microhematuria, were the clinical features, never accompanied by alteration of the renal function.
Abdominal Pain↗
CD5 B cells in autoimmune and non immune-mediated thyroid dysfunctions.
In a previous study we demonstrated a significant increase of CD5+ B subset in patients with Graves' disease (GD) compared with normal controls. The aim of this study was to compare the percentage of CD5+ B and CD5- B cells in GD with that in different forms of autoimmune and non immune-mediated thyroid diseases. Seventy-two patients were studied: 28 patients with GD, 20 with silent thyroiditis (ST), 12 with Hashimoto's disease (HD), and 12 subjects affected by hyperthyroidism due to toxic adenoma (TA). Eleven out of 28 patients with GD were also evaluated after six months of methimazole treatment. The study was performed by cytometric analysis. In GD the percentage and the absolute number of CD5+ B cells were significantly increased compared with normal controls (42.5 +/- 18.2% versus 19 +/- 6.3%, p < 0.0001; 142 +/- 153.3/cmm versus 46.9 +/- 22/cmm, p < 0.003, respectively. CD5+ B cells tended to normalise after six months of treatment. In ST the percentage of CD5+ B cells was increased (28.6 +/- 10.2%); conversely the absolute number was in the normal range. Patients affected by HD did not show any significant modification in B cells and their subsets in comparison with controls. In TA, CD5+ B were 7.6 /- 4.4% and 14.3 /- 10.9/cmm. Our results demonstrated a marked increase in both percentage and absolute number of CD5+ cells, only in active GD. The expansion of CD5+ B cells could play a role in the immune imbalance present in this disease.
Adenoma↗
[The IgE system].
The IgE synthesis is regulated by a system of immunocompetent cells (B and T lymphocytes) and cytokines (IL-4, IFN gamma, IL-2, IL-5, IL-6) produced by T cells as a response to antigenic stimuli. IL-4 alone, or associated with other cytokines, determines the CD23+ receptor (FCERII) expression on monocytes-macrophages, eosinophiles, platelets, epidermidis Langerhans cells and B lymphocytes surfaces, inducing its cleavage in a Soluble Factor (IgE-BF), that increases the IgE synthesis. IFN-gamma, on the other hand, plays an inhibitory role on T-dependent phenomena, IL-4-mediated. In patients affected by atopic diseases, associated with oculorhinites, dermatitis and hyper-IgE syndrome, are found high serum levels of IgE, eosinophiles, and a large number of CD23+ cells: this indicates the hyper-reactivity of the IgE system and the IL-4 overproduction.
Animals↗
[Teichoplanin: a clinical study of treatment of serious infections in hospitalized patients].
The study was performed to evaluate the efficacy and the safety of teicoplanin in the treatment of serious Gram positive bacteria infections in hospitalized patients at high risk of complications. In a twelve month period, 13 patients were treated. Six of whom presented generalized infections with bacteremia and seven severe localized infections. Safety evaluation included pre, during and post treatment measurements of haematological and serum chemistry parameters. Clinical successes with microbiological eradication of pathogens were obtained in 11 out of 13 cases (84.6%). One persistence of infection (7.7%) and one Gram negative superinfection (7.7%) presented. Only in one patient we noted a transitory increase of creatinine level. Teicoplanin showed to be useful in the treatment of serious Gram positive infections in hospitalized patients.
Adult↗
[Increased plasma levels of endothelin in patints with essential arterial hypertension].
Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictive peptide. In this study the Authors measured in 25 subjects (15 with essential hypertension and 10 normal) plasma levels of endothelin-1. Patients with hypertension had significantly higher plasma ET-1 concentration than normal subjects (2.18 +/- 1.07 vs. 1.36 +/- 0.40 pg/ml, p < 0.02). Plasma arginine vasopressin, renin activity and aldosterone concentration did not show significant differences between hypertensive and normotensive subjects. These data suggest that ET-1 may be involved in the development or maintenance of hypertension.
Endothelins↗