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ID PMID Title PublicationDate abstract
9265572 Chronic atrophic gastritis and Helicobacter pylori infection in primary biliary cirrhosis: 1997 Feb BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by exocrine gland impairment. Up to now there have been no reports dealing with gastric mucosa involvement in this autoimmune condition, which is frequently associated with Sjögren's syndrome. The aim of this study was to investigate the morphologic, biochemical and immunological features of the gastric mucosa in PBC. METHODS: A cross-sectional study with matching was performed. Thirty-three PBC patients (30 F, 3 M, mean age 58 years; 17 with stage II-III, and 16 with stage IV disease) and 33 sex- and age-matched dyspeptic controls were included. Six biopsy specimens from the fundus (2), body (2) and antrum (2) were taken from all patients and controls. A serological assessment was performed for each subject, i.e. pepsinogen A (PGA), pepsinogen C (PGC), gastrin (G), and antibodies against Helicobacter pylori (anti-Hp IgG). RESULTS: Endoscopic gastritis was found in 22 PBC patients (66.6%). There was no difference between PBC patients and controls regarding the percentage of subjects with mild, moderate, severe or atrophic gastritis (AG). There was no difference in gastric mucosal involvement between PBC subjects with or without secondary Sjögren's syndrome. A discrepancy was observed in the data obtained with respect to Helicobacter pylori (H. pylori) infection. H. pylori colonization was significantly more frequent in controls than in PBC patients (79% vs 49%, p < 0.002), but anti-Hp IgG were detected in the same percentage in the two groups (90% vs 83% respectively). There was no difference between the two groups in the PGA, PGC, PGA/PGC ratio, or gastrin. Eight PBC patients had esophageal varices. CONCLUSIONS: PBC patients are not characterized by chronic atrophic gastritis. Even though they present chronic gastritis with the same prevalence as dyspeptic controls, and show signs of previous H. pylori infection as frequently as dyspeptic patients, they are actually much less frequently infected. The reasons for this observation are unclear.
9811059 Effects of methotrexate on differentiation of monocytes and production of cytokine inhibit 1998 Nov OBJECTIVE: To examine the potential of methotrexate (MTX) to act as a differentiation-stimulating factor for monocytes, which could explain the antiinflammatory properties of this agent in the treatment of rheumatoid arthritis (RA). METHODS: Fluorescence-activated cell sorter analysis was used to measure the changes in antigen expression (CD11b/c, CD16, CD64, CD14, CD68, and CD95) in response to MTX, 1,25-OH-cholecalciferol (1,25-OH-CCF), and granulocyte-macrophage colony-stimulating factor in the human monoblastic leukemia cell line U937, bone marrow mononuclear cells (BMMC), and peripheral blood mononuclear cells (PBMC). Release of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), tumor necrosis factor a, and soluble tumor necrosis factor receptors (sTNFR) p55 and p75 during the differentiation in vitro was assessed by immunoassay in the culture supernatants. RESULTS: MTX alone and in combination with 1,25-OH-CCF markedly stimulated the differentiation of the monocytic U937 cells and simultaneously increased Fas-antigen expression. Differentiation was associated with enhanced IL-1Ra and sTNFR p75 release from U937 cells. MTX had fewer effects on phenotypic differentiation of human BMMC and PBMC, but did stimulate IL-1Ra release and inhibit IL-1beta synthesis in BMMC. CONCLUSION: MTX acts as a strong differentiation factor for immature and undifferentiated monocytic cells. Differentiation in vitro is associated with an increase in natural cytokine inhibitor release and a simultaneous down-regulation of IL-1beta. These findings may explain the marked clinical antiinflammatory effects of MTX when used in the treatment of RA.
11182026 Circulating CD8+ T cells in polymyalgia rheumatica and giant cell arteritis: a review. 2001 Feb BACKGROUND AND OBJECTIVE: During the last few years, there have been several studies on T cell subsets in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), with conflicting results. Whereas some authors have found normal values of circulating CD8+ T cells, others have found a decreased number. Furthermore, in some studies, the level of CD8+ cells was found to be related to disease activity, and it has been proposed that a decrease of CD8+ T cells be used as a diagnostic criterion for PMR. The purpose of our study was to determine the value of assessing T cell subsets in PMR and GCA. METHODS: T lymphocyte subsets were determined by flow cytometry using a whole blood lysis technique in the following groups: 28 PMR and 6 GCA patients before corticosteroid treatment, 20 PMR and 12 GCA patients in clinical remission with steroid treatment, 55 PMR patients in remission without steroid treatment, 17 rheumatoid arthritis (RA) patients before treatment, and 18 age-matched controls with noninflammatory conditions. Total white cell, lymphocyte, and platelet counts, hemoglobin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were measured by routine techniques. Comparisons were made by the Student's t-test and the Mann-Whitney test. A MEDLINE database search for studies published between 1983 and 1997 was performed. RESULTS: Compared with noninflammatory controls, CD8+ T cells were not reduced before steroid treatment in patients with active PMR/GCA in proportion (P =.7) or absolute numbers (P =.1). Patients with active disease had significantly lower hemoglobin levels and higher platelet counts, CRP, and ESR than noninflammatory controls (P <.05). When compared with active RA, CD8+ T cells were not reduced in patients with active PMR in proportion (P =.5) or absolute numbers (P =.2). Between these two groups, RA patients were significantly younger (P =.003) and had lower ESR values (P =.003). We did not find significant differences between patients with active PMR/GCA and those in remission with steroid therapy, except for the lower hemoglobin levels and higher platelet count, CRP, and ESR in the active disease group (P <.05). The same results were found when patients with active disease were compared with PMR in remission and no longer on steroid therapy, the only significant differences were those parameters reflecting the acute phase response (hemoglobin levels, platelet count, CRP and ESR). CONCLUSIONS: This study does not confirm the previous findings that the proportion or number of circulating CD8+ T cells are reduced in patients with active PMR/GCA. The utility of the determination of CD8+ T cells for diagnostic and prognostic purpose should be evaluated in a large multicenter study.
11591123 Induction of salivary gland epithelial cell injury in Sjogren's syndrome: in vitro assessm 2001 Sep Sjogren's syndrome (SS) is an exocrinopathy characterized by T cell infiltrates, salivary gland epithelial cell (SGEC) apoptosis and high Fas and FasL expression. To address the participation of T cell-derived cytokines and of Fas apoptotic pathway in SS glandular lesions, we utilized non-neoplastic SGEC lines established from SS patients and controls. Possibly attesting to their intrinsic activation, cell lines derived from SS patients displayed significantly higher constitutive Fas and FasL than controls. Surface co-expression of Fas and FasL was not associated with spontaneous fratricide apoptosis. SGEC were resistant to anti-Fas-mediated apoptosis (possibly owing to the constitutive expression of anti-apoptotic proteins cFLIP and Bcl-2), but became sensitive after protein or RNA synthesis inhibition. IFN-gamma and TNF-alpha were able to upregulate surface Fas and FasL, whereas IL-1beta downregulated surface FasL. IFN-gamma (but not several other cytokines) reduced the survival of SGEC in a dose- and time-dependent manner and induced Fas/FasL-mediated apoptosis, directly and via anoikia. Dexamethasone inhibited the upregulation of Fas and FasL by IFN-gamma and the induction of SGEC apoptosis and detachment by anti-Fas mAb or IFN-gamma. Our findings indicate the injurious role of IFN-gamma for the salivary epithelia of SS patients through the induction of Fas-mediated apoptosis and anoikia.
11669163 Clinical and laboratory features of anticentromere antibody positive primary Sjögren's sy 2001 Oct OBJECTIVE: To determine whether the clinical and laboratory characteristics of anticentromere antibody (ACA) positive, anti-SSA/Ro antibody (SSA) negative primary Sjogren's syndrome (SS) differ from SSA positive, ACA negative primary SS. METHODS: Twelve patients with ACA positive primary SS (ACA SS) and 19 patients with SSA positive primary SS (SSA SS) were examined. We compared the age, laboratory data, proportion with Raynaud's phenomenon (RP), activity of natural killer cells (NK), titer of antibodies against Epstein-Barr virus, and histological findings of minor labial salivary glands. The presence of anti-chromo antibodies (AChA) was evaluated by immunoblotting of patients' sera. RESULTS: The mean age of the ACA SS group was higher than that of the SSA SS group (p < 0.05). Serum IgG level was lower in ACA SS than in SSA SS (p < 0.0001). Serum IgG level of the ACA SS group with one exception was close to the normal range. Leukocytopenia was less frequently observed in ACA SS than in SSA SS (p < 0.05). RP was seen more frequently in the ACA SS group than the SSA SS group (p < 0.05). NK activity of the ACA SS group was higher than that of the SSA SS group (p < 0.05). Most of the ACA SS patients' NK activity was normal, in contrast to the tendency for NK activity in SS to be low. Virus capsid antigen IgA titer of the ACA SS group was lower than that of the SSA SS group (p < 0.05). Histological findings of minor labial salivary glands of both groups showed a similar severity of lymphocytic infiltrates, destruction of normal structures, and pattern of infiltrating lymphocyte subsets. AChA was positive in 11 of the 12 sera of ACA SS patients. CONCLUSION: The results confirm that ACA positive primary SS differs from SSA positive classic SS in several significant respects.
10776689 Rheumatoid factors in systemic lupus erythematosus: association with clinical and laborato 2000 The prevalence and clinical and laboratory associations of IgM, IgG and IgA rheumatoid factors (RF) were determined in 352 patients with systemic lupus erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.5%, and 20.5% of the sera, respectively. RF were associated with sicca syndrome, hypergammaglobulinemia, high titer of antinuclear antibodies, anemia, SSA- and SSB-antibodies, and with the presence of HLA-DR3. RF correlated negatively with nephritis and livedo racemosa. Moreover, we observed an association of RF and parameters of inflammatory activity such as elevated erythrocyte sedimentation rate (ESR) and leukopenia. Analysis of immunoglobulin classes revealed that laboratory parameters of inflammatory activity, SSA- and SSB-antibodies and HLA-DR3 correlated with IgA RF only. IgA RF define a subgroup of SLE patients characterized by distinct autoimmune phenomena and high disease activity in the absence of nephritis.
9647257 SB 203580 inhibits p38 mitogen-activated protein kinase, nitric oxide production, and indu 1998 Jul 1 Nitric oxide (NO) is implicated in a number of inflammatory processes and is an important mediator in animal models of rheumatoid arthritis and in in vitro models of cartilage degradation. The pyridinyl imidazole SB 203580 inhibits p38 mitogen-activated protein (MAP) kinase in vitro, blocks proinflammatory cytokine production in vitro and in vivo, and is effective in animal models of arthritis. The purpose of this study was to determine whether SB 203580 could inhibit p38 MAP kinase activity, NO production, and inducible NO synthase (iNOS) in IL-1 stimulated bovine articular cartilage/chondrocyte cultures. The results indicated that SB 203580 inhibited both IL-1 stimulated p38 MAP kinase activity in isolated chondrocytes and NO production in bovine chondrocytes and cartilage explants with an IC50 value of approximately 1 microM. To inhibit NO production, SB 203580 had to be present in cartilage explant cultures during the first 8 h of IL-1 stimulation, and activity was lost when it was added 24 h following IL-1. SB 203580 did not inhibit iNOS activity, as measured by the conversion of arginine to citrulline, when added directly to cultures where the enzyme had already been induced, but had to be present during the induction period. Using a 372-bp probe for bovine iNOS we demonstrated inhibition of IL-1-induced mRNA by SB 203580 at both 4 and 24 h following IL-1 treatment. The iNOS mRNA levels were consistent with NO levels in 24-h cell culture supernatants of the IL-1-stimulated bovine chondrocytes used to obtain the RNA.
9433878 Effects of Tripterygium wilfordii hook F extracts on induction of cyclooxygenase 2 activit 1998 Jan OBJECTIVE: Extracts of the Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) have been reported to be effective in the treatment of patients with a variety of inflammatory and autoimmune diseases, but the mechanism of this therapeutic effect has not been completely delineated. The present study was designed to assess the effects of TWHF on the in vitro synthesis of prostaglandin E2 (PGE2) and on the expression of the cyclooxygenase isoforms, COX-1 and COX-2, in various human cell types. METHODS: Monocytes from human peripheral blood (HM), fibroblasts from rheumatoid arthritis synovial tissue (RASF), human neonatal foreskin fibroblasts (HFF), and the histiocytic cell line U937 were cultured for designated time periods with or without lipopolysaccharide (LPS), and in the presence or absence of varying concentrations of the following inhibitors: the methanol/chloroform (T2) extract of TWHF, the ethyl acetate (EA) extract of TWHF, a purified diterpenoid component of TWHF (triptolide), dexamethasone, and indomethacin. Culture supernatants were harvested for PGE2 content assays. Total RNA was extracted from the cells and analyzed for COX-1 and COX-2 messenger RNA (mRNA) expression using reverse transcriptase-polymerase chain reaction or Northern blotting. RESULTS: Both the T2 and EA extracts inhibited PGE2 synthesis in the LPS-stimulated HM, RASF, and HFF cells, which was reflected by a marked suppression in the levels of mRNA for COX-2. In contrast, neither extract inhibited PGE2 production in U937 cells that did not express COX-2. Triptolide also inhibited LPS-stimulated induction of COX-2 mRNA and synthesis of PGE2, at the same inhibitory concentration as seen with the EA extract. The effects of T2, EA, and triptolide paralleled the inhibitory action of dexamethasone. CONCLUSION: The data indicate that both the T2 and EA extracts of TWHF, as well as the triptolide component, inhibit PGE2 production in a variety of human cells by blocking the up-regulation of COX-2.
11858705 The effects of deimination of myelin basic protein on structures formed by its interaction 2001 Oct The recombinant 18.5-kDa charge isoform of murine myelin basic protein (rmMBP) is unmodified posttranslationally and was used to study the effects of deimination, i.e., the conversion of arginyl to citrullinyl residues, on the protein's interactions with itself and with lipids. The unmodified species rmMBP-Cit(0) (i.e., containing no citrullinyl residues) interacted with binary monolayers containing acidic (phosphatidylinositol) and nickel-chelating lipids to form paracrystalline arrays with 4.8-nm spacing. A sample of protein was deiminated to an average of 9 citrullinyl residues per molecule of protein, yielding rmMBP-Cit(9). Under both low- and high-salt conditions, this species formed better-ordered domains than rmMBP-Cit(0), viz., planar crystalline assemblies. Thus, deimination of MBP resulted in a significant alteration of its lipid-organizing and self-interaction properties that might be operative in myelin in vivo, especially in progression of the autoimmune disease multiple sclerosis. Comparisons of amino acid sequences indicated significant similarities of MBP with filaggrin, a protein that is deiminated in another autoimmune disease, rheumatoid arthritis, suggesting that comparable epitopes could be targeted in both pathologies. In contrast, binary lipid monolayers consisting of phosphatidylinositol-4-phosphate (or phosphatidylinositol-4,5-bisphosphate) and a nickel-chelating lipid formed helical tubular vesicular structures, which appeared to be induced and/or stabilized by rmMBP, especially in its deiminated form. Sequence comparisons with other actin- and phosphoinositide-binding proteins (vinculin, ActA, MARCKS) suggested that the carboxyl-terminal segment of MBP could form an amphipathic alpha helix and was the phosphoinositide binding site.
11447291 A mutant cholera toxin B subunit that binds GM1- ganglioside but lacks immunomodulatory or 2001 Jul 17 GM1-ganglioside receptor binding by the B subunit of cholera toxin (CtxB) is widely accepted to initiate toxin action by triggering uptake and delivery of the toxin A subunit into cells. More recently, GM1 binding by isolated CtxB, or the related B subunit of Escherichia coli heat-labile enterotoxin (EtxB), has been found to modulate leukocyte function, resulting in the down-regulation of proinflammatory immune responses that cause autoimmune disorders such as rheumatoid arthritis and diabetes. Here, we demonstrate that GM1 binding, contrary to expectation, is not sufficient to initiate toxin action. We report the engineering and crystallographic structure of a mutant cholera toxin, with a His to Ala substitution in the B subunit at position 57. Whereas the mutant retained pentameric stability and high affinity binding to GM1-ganglioside, it had lost its immunomodulatory activity and, when part of the holotoxin complex, exhibited ablated toxicity. The implications of these findings on the mode of action of cholera toxin are discussed.
11357886 Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation me 2001 Apr The objective of this study was to investigate the therapeutic potential of FK506 and other immunosuppressive agents for the treatment of rheumatoid arthritis (RA), focusing on the effects on in vitro IL-6 production and IL-6-mediated immune response. We employed an in vitro model producing IL-6 via T cell activation in human PBMC, based on the hypothesis that T cells play a central role in the pathogenesis of RA. FK506 potently inhibited IL-6 production from PBMC stimulated with anti-CD3 and anti-CD28 monoclonal antibody (anti-CD3/CD28). Cyclosporin A (CsA) also inhibited the anti-CD3/CD28 induced IL-6 production but was about 100 times less potent than FK506. Dexamethasone (DEX) inhibited both anti-CD3/CD28 and LPS induced IL-6 production at almost the same concentration. Methotrexate (MTX) did not affect cytokine production. Anti-CD3/CD28 stimulated PBMC culture supernatants were found to enhance IgM production in SKW6.4 cells. The effects of anti-CD3/CD28 stimulated culture supernatants in the presence of agents on IgM production in SKW6.4 cells were investigated. FK506 and CsA led to suppression of IgM production induced by culture supernatants probably via inhibition of IgM inducible cytokine production from PBMC. DEX profoundly enhanced IgM production, although IL-6 production from PBMC was strongly inhibited by the agent. MTX decreased IgM production although it has no inhibitory effect on IL-6 production. The present study suggests that FK506 is the most effective among the four agents for the suppression of IL-6 production and IL-6-mediated autoantibody production in T cell activation related autoimmune diseases such as RA.
11290751 The cathepsin B inhibitor z-FA.fmk inhibits cytokine production in macrophages stimulated 2001 Jun 15 Cathepsin B has previously been shown to proteolytically activate the proinflammatory caspase-11 in vitro. Here we show that cathepsin B is not involved in activation of caspase-11 induced by lipopolysaccharide (LPS) and subsequent maturation of interleukin (IL)-1beta in macrophages. Nevertheless, we found that the cathepsin B inhibitor benzyloxycarbonyl-Phe-Ala-fluoromethylketone (z-FA.fmk) prevents LPS-induced production of IL-1alpha, IL-1beta, and tumor necrosis factor at the transcriptional level. The latter was not because of cathepsin B inhibition, but was mediated by inhibition of the transactivation potential of the nuclear factor kappaB (NF-kappaB). z-FA.fmk did not prevent LPS-induced activation of p38 mitogen-activated protein kinase, which was shown to be involved in NF-kappaB transactivation in response to LPS. These results suggest that the previously described therapeutic effect of z-FA.fmk in the treatment of rheumatoid arthritis might not only result from inhibition of cathepsin B but also implicates an important contribution from the inhibition of NF-kappaB-dependent gene expression.
11248219 Inactivation of creatine kinase during the interaction of indomethacin with horseradish pe 2001 Mar 14 Creatine kinase (CK) was used as a marker molecule to examine the side effect of damage to tissues by indomethacin (IM), an effective drug to treat rheumatoid arthritis and gout, with horseradish peroxidase and hydrogen peroxide (HRP-H2O2). IM inactivated CK during its interaction with HRP-H2O2. Under aerobic conditions, inactivation of CK significantly decreased. CK in rat heart homogenate was also inactivated by IM with HRP-H2O2. When IM was incubated with HRP-H2O2, the maximum absorption of IM at 280 nm rapidly decreased and a new peak at 410 nm occurred with isosbestic points at 260 and 312 nm. In contrast, under anaerobic conditions, the spectral change of IM was almost absent, indicating IM was oxidized to the yellow substance by HRP-H2O2. Adding catalase strongly inhibited the production of yellow substance. Sodium azide also blocked the formation of yellow substance and the inactivation of CK. Electron spin resonance signals of IM carbon-centered radical were detected using 2-methyl-2-nitrosopropane during the interaction of IM with HRP-H2O2 under anaerobic conditions. Oxygen was consumed during the interaction of IM with HRP-H2O2. These results suggest that IM carbon-centered radicals may rapidly react with O2 to generate the peroxyl radicals. Sulfhydryl groups and tryptophane residues of CK decreased during the interaction of IM with HRP-H2O2. Other sulfhydryl enzymes, including alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, were also readily inactivated during the interaction with HRP-H2O2. Sulfhydryl enzymes seem to be very sensitive to IM activated by HRP-H2O2.
11121721 Synergistic inhibition of cyclooxygenase-2 expression by vitamin E and aspirin. 2000 Dec The use of aspirin in rheumatoid arthritis is limited since inhibition of the pro-inflammatory enzyme cyclooxygenase-2 occurs only at higher aspirin doses that are often associated with side effects such as gastric toxicity. Using a macrophage cell line (J774. 1A), the present study explores possible synergistic effects of aspirin and vitamin E on the expression and activity of cyclooxygenase-2. Lipopolysaccharide-induced prostaglandin E(2) formation was significantly reduced by aspirin (1-100 microM) or vitamin E (100-300 microM). When combined with vitamin E, aspirin-dependent inhibition of prostaglandin E(2) formation was increased from 59% to 95% of control. Likewise, lipopolysaccharide-induced cyclooxygenase-2 protein and mRNA expression were virtually abolished by the combined treatment of aspirin and vitamin E, whereas the two agents alone were only modestly effective. Vitamin C did not mimic the actions of vitamin E under these conditions, suggesting that redox-independent mechanisms underlie the action of vitamin E. In agreement with this, vitamin E and aspirin were without effect on lipopolysaccharide-induced translocation of the redox-sensitive transcription factor NF-kappa B. Our results show that co-administration of vitamin E renders cyclooxygenase-2 more sensitive to inhibition by aspirin by as yet unknown mechanisms. Thus, anti-inflammatory therapy might be successful with lower aspirin doses when combined with vitamin E, thereby possibly avoiding the side effects of the usually required high dose aspirin treatment.
10690833 The surgical management of hypotony. 2000 Feb OBJECTIVE: To study the effect of dissecting epiciliary proliferative tissue in eyes that are hypotonous. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Eight patients (nine eyes). MAIN OUTCOME MEASURES: Normalization of intraocular pressure and preservation of vision. METHODS: A chart review was conducted to locate all surgical procedures performed primarily for hypotony. Nine procedures on eight eyes of eight patients seen in the vitreoretinal service of the Wilmer Ophthalmological Institute were identified and included in this study. Six of these eyes had undergone prior surgery for retinal detachment in association with proliferative vitreoretinopathy, one had undergone surgery for retinal detachment in the setting of a ruptured globe, and two had undergone cataract surgery and coined the diagnoses of uveitis (juvenile rheumatoid arthritis and sarcoid). Dissection and removal of the epiciliary proliferative tissue and lens capsule was undertaken by two surgeons (EdJ and MSH) using either a pars plana or limbal approach. The main outcome measures were intraocular pressure (IOP) and visual acuity after an average follow-up of 26 months (range, 9-48 months). RESULTS: In the immediate postoperative period, all patients showed an increase in IOP (average increase of 6.3 mm Hg; range, 3-14 mmHg). This average increase in IOP decreased to 5.2 mmHg at 6 months and 4.2 mm Hg at 12 or more months of follow-up. The rate of the IOP decrease appeared to lessen with time, suggesting long-term stabilization. Visual acuity remained stable in all patients, although the final level of vision was low. CONCLUSIONS: Surgical intervention for hypotony with greater than 1 year follow-up continues to show elevated IOP in some patients, despite the fact that the large initial increase in IOP is not sustained. No eye had phthisis develop or became painful. However, no eye had marked improvement in vision. Further study is needed to uncover the main contributing factors that result in hypotony before IOP can be maintained for prolonged periods in more hypotonous eyes and before these eyes can regain more vision.
10620073 Evidence for a pathogenic role of nitric oxide in inflammation-induced osteoporosis. 1999 Dec Inflammatory disease is associated with increased production of nitric oxide (NO) and activation of the inducible nitric oxide synthase (iNOS) pathway. Several studies have addressed the role of NO as a mediator of cytokine effects on bone cell activity in vitro. Stimulatory and inhibitory actions have been found, however, depending on the concentrations produced and model system used. In view of this, it has been difficult to predict whether increased production of NO during inflammation is likely to increase bone loss or prevent it. We have investigated the pathogenic role of NO in an animal model of inflammation-induced osteoporosis (IMO). NO production was increased in IMO when compared with controls (+344%; p < 0.01), and this was accompanied by activation of inducible NOS (iNOS) in the bone marrow space. Bone mineral density (BMD) was reduced in IMO when compared with controls (-64%; p < 0.01), and this was found to be associated with reduced osteoblast numbers (-44%; p < 0.05) and increased osteoclast numbers (+38%; p < 0.01). The NOS inhibitor L-NMMA reversed the deleterious effects of IMO on bone mass and bone turnover, but L-NMMA had no effect on bone mass in control animals. This study has important implications for many inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease which are associated with increased NO production and osteoporosis. Our data not only suggest that iNOS activation and increased NO production contribute to the pathogenesis of osteoporosis in these situations, but also suggest that NOS inhibitors could be of therapeutic value in the prevention and treatment of such bone loss.
10608273 Niacinamide therapy for osteoarthritis--does it inhibit nitric oxide synthase induction by 1999 Oct Fifty years ago, Kaufman reported that high-dose niacinamide was beneficial in osteoarthritis (OA) and rheumatoid arthritis. A recent double-blind study confirms the efficacy of niacinamide in OA. It may be feasible to interpret this finding in the context of evidence that synovium-generated interleukin-1 (IL-1), by inducing nitric oxide (NO) synthase and thereby inhibiting chondrocyte synthesis of aggrecan and type II collagen, is crucial to the pathogenesis of OA. Niacinamide and other inhibitors of ADP-ribosylation have been shown to suppress cytokine-mediated induction of NO synthase in a number of types of cells; it is therefore reasonable to speculate that niacinamide will have a comparable effect in IL-1-exposed chondrocytes, blunting the anti-anabolic impact of IL-1. The chondroprotective antibiotic doxycycline may have a similar mechanism of action. Other nutrients reported to be useful in OA may likewise intervene in the activity or synthesis of IL-1. Supplemental glucosamine can be expected to stimulate synovial synthesis of hyaluronic acid; hyaluronic acid suppresses the anti-catabolic effect of IL-1 in chondrocyte cell cultures, and has documented therapeutic efficacy when injected intra-articularly. S-adenosylmethionine (SAM), another proven therapy for OA, upregulates the proteoglycan synthesis of chondrocytes, perhaps because it functions physiologically as a signal of sulfur availability. IL-1 is likely to decrease SAM levels in chondrocytes; supplemental SAM may compensate for this deficit. Adequate selenium nutrition may down-regulate cytokine signaling, and ample intakes of fish oil can be expected to decrease synovial IL-1 production; these nutrients should receive further evaluation in OA. These considerations suggest that non-toxic nutritional regimens, by intervening at multiple points in the signal transduction pathways that promote the synthesis and mediate the activity of IL-1, may provide a substantially superior alternative to NSAIDs (merely palliative and often dangerously toxic) in the treatment and perhaps prevention of OA.
10393445 Autoantibodies against oxidatively modified low-density lipoprotein in patients with Behç 1999 BACKGROUND: Change of lipids and lipoprotein metabolism and an imbalance of the oxidant-antioxidant system related to the disease activity have been reported in Behçet's disease. Therefore, there is a tendency of oxidative modification of lipids and lipoproteins in patients with the disease. OBJECTIVE: To investigate serum autoantibodies against oxidatively modified low-density lipoprotein (oxLDL) as a marker for the degree of in vivo oxidation of lipoproteins in Behçet's disease. METHODS: Serum autoantibodies against oxLDL, total cholesterol, triacylglycerol, HDL cholesterol, LDL cholesterol, apolipoprotein (Apo) AI, Apo B, alpha1-antitrypsin, alpha2-macroglobulin and erythrocyte sedimentation rate were determined in 37 patients and 30 sex- and age-matched healthy volunteers. Autoantibodies against oxLDL were measured by a commercial enzyme-linked immunosorbent assay. RESULTS: Serum autoantibody levels against oxLDL were significantly higher in patients than in controls (425 +/- 365 and 187 +/- 132 mU/ml, respectively; p < 0.05). The levels of autoantibodies against oxLDL in the patients were found to correlate with total cholesterol, LDL cholesterol, HDL cholesterol and alpha1-antitrypsin levels (r = 0.38, p < 0.05; r = 0.42, p < 0.05; r = -0.38, p < 0.05; r = 0.42, p < 0. 05, respectively). CONCLUSION: It has been shown in previous studies that high autoantibody titers against oxLDL may be important in diseases with atherosclerosis as seen in systemic lupus erythematosus and rheumatoid arthritis. High autoantibody titers against oxLDL are not specific for Behçet's disease but probably important for pathologic processes in the disease. We suggest that increased levels of autoantibodies against oxLDL may be a factor responsible for endothelial dysfunction and development of vascular pathology in Behçet's disease.
10227815 Synergistic inhibition of human B cell activation by gold sodium thiomalate and auranofin. 1999 May The mechanism of action of gold compounds, which are effective in the treatment of rheumatoid arthritis (RA), has not been clearly identified. Since one of the characteristic features of RA is chronic stimulation of B cells, the current studies compared the effects of parenteral gold (gold sodium thiomalate; GST) and orally active gold (auranofin; AUR) on human B cells. IgM production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. T cell proliferation and IFN-gamma production was induced from highly purified T cells by stimulation with immobilized mAb to CD3. AUR as well as GST suppressed B cell IgM production at much lower concentrations than those that suppressed T cell proliferation or IFN-gamma production. Thus, as little as 0.01 microg/ml AUR (0.015 microM) markedly suppressed IgM production, but neither T cell proliferation nor IFN-gamma production. AUR as well as GST is required at the initiation of cultures to exert optimal suppressive effects on IgM production. Moreover, AUR as well as GST suppressed the expression of CD98 and CD71 on SA-stimulated B cells. Of note, AUR and GST exerted a synergistic inhibitory effect on B cell production of IgM and IgG in a manner which was reversed by catalase, but not by ascorbate. The synergistic inhibitory effect is most likely to be due to thiomalate components of GST, since AUR and thiomalate exerted comparable synergistic inhibitory effects on B cell function. Finally, AUR and bucillamine, another antirheumatic drug with thiol groups, also showed synergistic inhibition of B cell function. These results indicate that AUR and GST preferentially inhibit the function of B cells by interfering with the initial activation of B cells. More importantly, the data indicate that AUR synergizes with GST or thiols to inhibit B cell function in a manner that depends upon the generation of hydrogen peroxide. These synergistic inhibitory effects of AUR and compounds with thiols on in vitro human B cell activation suggest the therapeutic efficacy of combinations of these compounds in RA.
9820804 Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the ac 1998 Dec 1 Leflunomide is currently in phase-III clinical trials for the treatment of rheumatoid arthritis. In this study, we have focused our efforts on the study of the mechanism of action of the active metabolite of leflunomide, A77 1726, in cells and tissue of human origin. The human high-affinity binding protein for radiolabelled A77 1726 was purified from solubilized U937 membranes by following the binding activity through the purification process and was characterized as the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH). The human and murine enzyme displayed identical pI and molecular mass values on SDS/PAGE (43 kDa), which contrasts notably with previous reports suggesting a molecular mass of 50 kDa for the human enzyme. DHO-DH activity was inhibited by A77 1726 and its analogue HR325 with similar potency in U937 and human spleen membrane preparations. HR325 was found to be anti-proliferative for phytohaemagglutinin-stimulated human peripheral blood mononuclear cells, at the same concentrations that caused accumulation of DHO and depletion of uridine. Supplementation of the cultures with exogenous uridine led to partial abrogation of the anti-proliferative effect. This is in line with our recent demonstration that the anti-proliferative effect in vitro of A77 1726 on lipopolysaccharide-stimulated mouse spleen cells was mediated by DHO-DH inhibition [Williamson, Yea, Robson, Curnock, Gadher, Hambleton, Woodward, Bruneau, Hambleton, Moss et al., (1995) J. Biol. Chem. 270, 22467-22472]. Thus, DHO-DH inhibition by A77 1726 and its analogues is responsible for the anti-proliferative effects in vitro of the compounds on human cells and is likely to be responsible for some of its effects in vivo.