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ID PMID Title PublicationDate abstract
17082575 Antibody responses to mycobacterial and self heat shock protein 65 in autoimmune arthritis 2006 Nov 15 Many autoimmune diseases are believed to involve primarily T cell-mediated effector mechanisms. There is increasing realization, however, that Abs may also play a vital role in the propagation of T cell-driven disorders. In this study, on the rat adjuvant-induced arthritis (AA) model of human rheumatoid arthritis, we examined the characteristics of serum Ab response to mycobacterial heat shock protein (hsp) 65 (Bhsp65), self (rat) hsp65 (Rhsp65), and linear peptides spanning these two molecules. The AA-resistant WKY (RT.1(l)) rat responded to the heat-killed Mycobacterium tuberculosis immunization with a rapid burst of Abs to both Bhsp65 and Rhsp65. These Abs reacted with numerous peptide epitopes; however, this response was reduced to a few epitopes with time. On the contrary, the susceptible Lewis (RT.1(l)) rat developed a relatively lower Ab response to Bhsp65, and Abs to Rhsp65 did not appear until the recovery from the disease. The Ab response in Lewis rats diversified with progression of AA, and there was an intriguing overlap between the repertoire of Bhsp65-reactive B and T cells during the recovery phase of AA. Nonetheless, subsets of the repertoire of the late Abs in both rat strains became focused on the same epitope regions of Bhsp65 and Rhsp65. The functional relevance of these Abs was evident from the results showing that sera from recovery phase Lewis or WKY rats, but not that of naive rats, afforded protection against subsequent AA. These results are of significance in further understanding of the role of humoral immunity in the pathogenesis of autoimmune arthritis.
17114500 Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition. 2006 Dec 1 A hallmark of T cell-mediated autoimmunity is the persistence of autoreactive T cells. However, it remains to elucidate the manner in which synovial T cells are sustained in patients with rheumatoid arthritis (RA). We found that dendritic cells (DC) and tissues from the synovial joints of RA patients expressed higher levels of IDO than DC from healthy donors. Interestingly, T cells derived from the joint synovial fluid (SF) of RA patients proliferated in response to either autologous or allogeneic IDO-positive DC, an outcome that was not affected by the addition of IDO inhibitor 1-methyl-D-tryptophan (1-MT). In contrast, addition of 1-MT to the culture stimulated with allogeneic or autologous IDO-positive DC significantly enhanced the proliferation of T cells derived from peripheral blood of healthy donors or from peripheral blood of RA patients. Furthermore, we found that functionally active tryptophanyl-tRNA-synthetase (TTS) was significantly elevated in T cells derived from the SF of RA patients, leading to enhanced storage of tryptophan in T cells and to subsequent resistance to IDO-mediated deprivation of tryptophan. The RA SF enhancement of TTS expression in T cells was blocked by mAb to IFN-gamma and TNF-alpha. These results suggest that the resistance of T cells to IDO-mediated deprivation of tryptophan represents a mechanism by which autoreactive T cells are sustained in vivo in RA patients. Specifically, blocking of the up-regulation of TTS expression in T cells presents an avenue for development of a novel therapeutic approach to treatment of RA.
15772594 Clinical and radiographic findings of the temporomandibular joint in patients with various 2005 Apr OBJECTIVES: To investigate subjective, clinical and radiographic findings relating to the temporomandibular joint (TMJ) in patients with rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), ankylosing spondylitis (AS), and spondyloarthropathy (SPA), and to compare the findings with those in age- and sex-matched control subjects. STUDY DESIGN: Eighty patients (24 with RA, 16 with MCTD, 19 with AS, 21 with SPA) and 80 matched controls participated in the study. Replies to a questionnaire covering oral and TMJ symptoms were analysed in conjunction with medical histories, results of clinical examination of the stomatognathic system, and panoramic and lateral panoramic radiographs. RESULTS: Patients with rheumatic disease reported severe TMJ symptoms significantly oftener than control subjects (P < .001). Patients with AS reported symptoms most frequently (7/19, 37%). Mean maximal opening of the mouth (SD) was significantly less in patients with rheumatic disease (46.3 mm (8.6 mm)) than in control subjects (55.0 mm (7.4 mm)) (P < .001). Marked erosions were observed in 4 RA patients (17%), 3 MCTD patients (19%), 8 SPA patients (38%), 7 AS patients (37%), and 1 control subject (1%) (P < .001). The existence of erosion was associated with evidence of restricted movement of condyle in panoramic radiographs (P < .001). There was correlation between radiographic findings relating to the TMJ and subjective and clinical stomatognathic-system symptoms in patients with rheumatic disease. Subjective TMJ symptoms were associated with evidence of restricted movement of condyle in panoramic radiographs (P < .001). Impairment of laterotrusion movement was significantly associated with erosion (P < .001). CONCLUSIONS: The TMJ is commonly affected in patients with RA, and in patients with other forms of rheumatic disease. There are associations between radiographic findings and subjective symptoms, and between radiographic findings and restricted TMJ movement. In screening for suspected TMJ destruction, it would be appropriate to look for restricted maximal mouth opening, masticatory muscle tenderness and restricted laterotrusion.
16277680 Tumour necrosis factor-alpha stimulates dehydroepiandrosterone metabolism in human fibrobl 2005 Glucocorticoids have successfully been used in the treatment of rheumatoid arthritis. Data suggest that 7alpha-hydroxy-dehydroepiandrosterone (7alpha-OH-DHEA), an immunostimulating metabolite of dehydroepiandrosterone, can block glucocorticoid-induced immune suppression. Formation of 7alpha-OH-DHEA is catalyzed by activity of cytochrome p450 enzyme 7b (Cyp7b). Recently, we reported that tumour necrosis factor (TNF)-alpha, IL-1alpha, IL-1beta and IL-17 enhance Cyp7b mRNA expression and induce a concomitant increase in the formation of 7alpha-OH-DHEA by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis patients. The aim of this study was to elucidate which signal transduction pathway is involved in the TNF-alpha-mediated induction of Cyp7b activity in FLS. We studied the effects of inhibitors of different signal transduction pathways on Cyp7b activity in FLS by measuring Cyp7b mRNA expression using reverse transcription PCR and by measuring the formation of 7alpha-OH-DHEA. We applied SN50, an inhibitor of nuclear translocation of transcription factors (i.e. activator protein-1 [AP-1] and nuclear factor-kappaB [NF-kappaB]); PSI, a proteasome inhibitor that prevents IkappaB degradation and thereby NF-kappaB release; SP600125, a c-Jun N-terminal kinase (JNK) inhibitor; and the mitogen-activated protein kinase inhibitors PD98059 (extracellular signal-regulated kinase) and SB203580 (p38). Cyp7b is constitutively expressed in RA FLS and can be activated in response to TNF-alpha. SN50 and PSI prevented the TNF-alpha-induced increase in Cyp7b activity, whereas the mitogen-activated protein kinase inhibitors PD98059 and SB203580 had no effect. In addition, inhibition of Cyp7b mRNA expression and activity was observed with SN50, PSI and SP600125, suggesting that NF-kappaB and AP-1 induce Cyp7b transcription. These findings suggest that NF-kappaB and AP-1 are involved in the TNF-alpha-enhanced formation of the dehydroepiandrosterone metabolite 7alpha-OH-DHEA. Our results are in accordance with presence of AP-1 and NF-kappaB binding sites in the Cyp7b promoter.
15813418 Side effects of anticytokine strategies. 2005 Mar Anticytokine strategies probably represent the most important breakthrough in the treatment of inflammatory diseases in the last decade. However, blocking the bioactivity of proinflammatory cytokines, crucial activators of host defence, has proved to be accompanied by an increased susceptibility to infections, especially with Mycobacteria, Salmonellae and fungal pathogens. Multiple mechanisms for these side effects have been proposed, such as inhibition of gamma-interferon production, decreased expression of pattern-recognition receptors, and leucocyte apoptosis. Caution is therefore warranted when these treatments are given to patients with an increased risk for infections. A range of side effects other than infection have been reported.
16490847 Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alp 2006 Feb BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Accordingly, TNF-alpha inhibitors, such as thalidomide, infliximab (Remicade), adalimumab (Humira), and etanercept (Enbrel), have been used with success in the treatment of autoimmune disorders, including psoriasis, rheumatoid arthritis, inflammatory bowel diseases, and lymphoproliferative disorders. Although anti-TNF-alpha therapy is safe and well tolerated, various adverse cutaneous reactions have been reported. OBSERVATIONS: We encountered 5 patients who developed erythematous annular plaques on the trunk and extremities while receiving 4 different medications with inhibitory activity against TNF-alpha. One patient was treated with lenalidomide (Revlimid) for multiple myeloma, 2 received infliximab, and 1 received etanercept for severe rheumatoid arthritis; the last patient was in a clinical trial of adalimumab for psoriatic arthritis. Skin biopsy specimens revealed diffuse interstitial granulomatous infiltrates of lymphocytes, histiocytes, and eosinophils, palisading degenerated collagen. Withdrawal of the medications led to complete resolution of the skin lesions. CONCLUSION: Interstitial granulomatous dermatitis should be considered in the differential diagnosis of skin lesions occurring in the setting of anti-TNF-alpha therapy.
17299600 Inhibition of TWEAK activity as a new treatment for inflammatory and degenerative diseases 2006 Dec Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally-related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro including cell proliferation, migration, survival, differentiation and apoptosis. TWEAK is also a proangiogenic and proinflammatory factor in vivo. Recent studies have indicated that pharmacological inhibition of TWEAK activity may have therapeutic efficacy in several diseases including ischemic stroke, cerebral edema, multiple sclerosis and rheumatoid arthritis. In this review we first introduce the TWEAK-Fn14 signaling system and then focus on the potential therapeutic utility of soluble Fn14-Fc fusion proteins and TWEAK neutralizing antibodies.
16510746 Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalop 2006 Mar 2 BACKGROUND: Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients. METHODS: We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI. RESULTS: Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000). CONCLUSIONS: A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.
15897648 Felty's syndrome with chronic hepatitis and compatible autoimmune hepatitis: a case presen 2005 Apr A 68-year-old woman with Felty's syndrome was admitted to our hospital due to breathlessness. She was diagnosed as having rheumatoid arthritis at age 59 years. Abdominal computed tomography indicated ascites, splenomegaly and liver atrophy. She had no antigens or antibodies for hepatitis virus, or antibodies for mitochondria with the exception of antinuclear antibody. According to the International Autoimmune Hepatitis (AIH) scoring system, she was diagnosed as having chronic hepatitis, compatible with AIH. The association of Felty's syndrome with AIH is very rare and the most difficult problem to overcome is whether or not steroid therapy is necessary in patients with Felty's syndrome complicated by AIH.
17241583 Urticaria as a cutaneous sign of adult-onset Still's disease. 2006 Mar BACKGROUND: The cardinal signs and symptoms of adult-onset Still's disease (AOSD) include periodic fever, arthralgia and arthritis, lymphadenopathy, hepatosplenomegaly, an evanescent rash accompanied by neutrophilic granulocytosis, and a negative rheumatoid factor and antinuclear antibody test. OBJECTIVE: To alert clinicians and dermatologists to internal diseases such as AOSD when assisting patients with urticarial eruptions and systemic symptoms. METHODS: A case report of a 52-year-old white woman who received conventional therapy for urticaria for 3 years, with no improvement. Following this period, a diagnosis of AOSD was performed based on the presence of systemic symptoms. RESULTS: The inflammatory activity markers decreased by the second month of methotrexate therapy; however, the cutaneous lesions failed to disappear. Thalidomide was initiated, and total improvement of the cutaneous lesions was observed after 2 weeks. CONCLUSION: Urticarial rash is an uncommon presentation of AOSD, and clinicians must be alert to the possibility of a misdiagnosis in these cases.
15761492 Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. 2005 Apr Osteopontin (OPN) is an extracellular matrix protein of pleiotropic properties and has been recently recognized as a potential inflammatory cytokine. In this study, we demonstrate, for the first time to our knowledge, that overexpression of OPN in synovial T cells is associated with local inflammatory milieu and that OPN acts as an important mediator in amplification and perpetuation of rheumatoid synovitis. The study revealed that mRNA expression of OPN was highly elevated in CD4(+) synovial T cells derived from patients with RA, which correlated with increased OPN concentrations in synovial fluid (SF). The pattern of OPN overexpression was confined to rheumatoid synovium and correlated with coexpression of selected OPN receptors in synovial T cells, including integrins alphav and beta1 and CD44. RA-derived SF stimulated the expression of OPN in T cells, which was attributable to IL-10 present in SF and abrogated by anti-IL-10 antibody. Among the more than 300 autoimmune and inflammatory response genes examined, OPN selectively induced the expression of proinflammatory cytokines and chemokines known to promote migration and recruitment of inflammatory cells. Furthermore, it was evident that OPN activated transcription factor NF-kappaB in mononuclear cells. The study has important implications for understanding the role of OPN in rheumatoid synovitis and other inflammatory conditions.
17122493 Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes. 2006 Dec A broad and diverse spectrum of vasculitic syndromes exists. These syndromes affect the skin with varying levels of associated systemic manifestations, running the gamut from a self-limited, localized, cutaneous phenomenon to rapidly progressive, multiorgan disease. The majority of cases of cutaneous vasculitis will show a neutrophilic small vessel vasculitis that can be either a primary (idiopathic) disorder (eg, cutaneous leukocytoclastic angiitis) or a secondary disorder that is associated with drugs, infection (eg, streptococcal infection, viral hepatitis), or underlying disease (eg, connective tissue disease, malignancy). Biopsy is the gold standard for the diagnosis of cutaneous vasculitis and also necessary for the detection of cutaneous vascular immune complexes by direct immunofluorescence. Based on the type of vessel disrupted by inflammation (small and/or muscular), the distribution of vasculitis in the dermis and subcutis, and predominate inflammatory cell-type mediating vessel wall damage, a list of relevant differential diagnoses can be generated. This histologic information coupled with extravascular findings such as tissue eosinophilia, tissue neutrophilia, and/or granulomas, plus pathophysiologic markers such as direct immunofluorescent examination for immune complexes and serologic evaluation for antineutrophil cytoplasmic antibodies allows for more accurate diagnosis of specific vasculitic entities. Herein, we review both primary and secondary vasculitic syndromes that affect the skin and show a small vessel neutrophilic mediated vasculitis.
15751070 CYP7B expression and activity in fibroblast-like synoviocytes from patients with rheumatoi 2005 Mar OBJECTIVE: The cytochrome P450 enzyme CYP7B catalyzes the conversion of dehydroepiandrosterone (DHEA) into 7alpha-hydroxy-DHEA (7alpha-OH-DHEA). This metabolite can stimulate the immune response. We previously reported that the severity of murine collagen-induced arthritis is correlated with CYP7B messenger RNA (mRNA) expression and activity in the arthritic joint. The purpose of this study was to investigate the presence of 7alpha-OH-DHEA in synovial samples and the cytokine regulation of CYP7B activity in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: The presence of 7alpha-OH-DHEA was examined in synovial biopsy tissues, synovial fluid, and serum by radioimmunoassay. The effect of cytokines on CYP7B mRNA expression and CYP7B activity in FLS was examined by determining the formation of the CYP7B enzyme product 7alpha-OH-DHEA with the use of high-performance liquid chromatography. RESULTS: The CYP7B enzyme product 7alpha-OH-DHEA was found in synovial biopsy tissues, synovial fluid, and serum from RA patients. The proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-1alpha (IL-1alpha), IL-1beta, and IL-17 up-regulated CYP7B activity in an FLS cell line 2-10-fold. Enhanced CYP7B activity was correlated with an increase in CYP7B mRNA. The cytokine transforming growth factor beta inhibited CYP7B activity. Moreover, CYP7B activity was detected in 10 of 13 unstimulated synovial fibroblast cell lines. Stimulation with TNFalpha increased CYP7B activity in all cell lines tested. CONCLUSION: Exposure to the proinflammatory cytokines TNFalpha, IL-1alpha, IL-1beta, and IL-17 increases CYP7B activity in synovial tissue. Increased CYP7B activity leads to higher levels of the DHEA metabolite 7alpha-OH-DHEA in synovial fluid, which may contribute to the maintenance of the chronic inflammation observed in RA patients.
16142741 Effectiveness of anti-folate receptor beta antibody conjugated with truncated Pseudomonas 2005 Sep OBJECTIVE: To define the distribution of folate receptor beta (FRbeta)-expressing cells in various tissues, including rheumatoid arthritis (RA) synovial tissues, and to verify the effects of an immunotoxin composed of an anti-FRbeta monoclonal antibody (mAb) and truncated Pseudomonas exotoxin A (PEA) on apoptosis and tumor necrosis factor alpha (TNFalpha) production by adherent synovial mononuclear cells from RA patients. METHODS: Anti-FRbeta mAb were produced by immunizing mice with FRbeta-transfected murine pre-B cells. The distribution of the FRbeta antigen was examined by immunohistochemical analysis using anti-FRbeta mAb and macrophage-specific anti-CD163 mAb. Anti-FRbeta mAb was chemically crosslinked with truncated PEA. FRbeta-expressing macrophages were produced by the transfection of adenovirus vector containing the FRbeta gene. Apoptotic cells were detected by staining with propidium iodide. TNFalpha was measured by enzyme-linked immunosorbent assay. RESULTS: FRbeta-expressing cells were not present in peripheral blood leukocytes and their activated cells. In all of the tissues examined, most FRbeta-expressing cells were CD163+. The immunotoxin significantly induced the apoptosis of FRbeta-transfected macrophages and adherent RA synovial mononuclear cells and inhibited TNFalpha production by adherent RA synovial mononuclear cells. CONCLUSION: We demonstrated the limited distribution of FRbeta-expressing cells in various tissues. The immunotoxin targeting FRbeta-expressing cells will provide a therapeutic tool for rheumatoid synovitis.
17023807 Prevalence of evaluation and treatment of glucocorticoid-induced osteoporosis in men. 2006 Oct BACKGROUND: Screening and treatment of glucocorticoid- induced osteoporosis in male patients is less than recommended despite available screening and therapies. OBJECTIVES: We determined if men treated with long-term oral glucocorticoid therapy for any reason receive assessment and therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. METHODS: A retrospective computer-generated chart review was performed involving all men given prednisone from January 2002 through July 2002. There were 370 patients evaluated from the James A. Haley Veterans Affairs Hospital, Tampa, Florida, a large teaching hospital for the University of South Florida College of Medicine. Charts were reviewed for bone mineral density testing; dose, duration, and indication of glucocorticoid therapy; age of the patients as of January 2002;continuous or intermittent dosing; history of fracture; bone loss prevention medication use, including bisphosphonate, calcitonin, testosterone replacement therapy, calcium, and vitamin D; and the steroid-prescribing and screening practitioner's specialty and sex. RESULTS: Of the 370 men, 258 used 7.5 mg prednisone or more daily and 295 used glucocorticoids for more than 3 months. Of the 370 men, 163 had a bone mineral density test; 87 were treated with a bisphosphonate. Calcium and vitamin D were given to half of the patients. Of the patients with a normal T-score, 13 of 55 were treated with a bisphosphonate (24%) compared with 24 of 40 (60%) with an osteopenic score and 14 of 21 (67%) with osteoporosis. Of the 46 patients with no score available but indication that it had been ordered or otherwise addressed, 23 patients were treated empirically with a bisphosphonate. Rheumatology screened 75% of their patients, whereas primary care screened 30% of their patients. CONCLUSIONS: Bone mineral density testing was performed or ordered for less than half of the glucocorticoid-treated patients and less than one third were taking bisphosphonate therapy. Further intervention is needed to increase prevention of glucocorticoid-induced osteoporosis and subsequent risk of fracture.
16778989 A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH ox 2006 Jul Neutrophil NADPH oxidase plays a key role in host defense and in inflammation by releasing large amounts of superoxide and other ROSs. Proinflammatory cytokines such as GM-CSF and TNF-alpha prime ROS production by neutrophils through unknown mechanisms. Here we used peptide sequencing by tandem mass spectrometry to show that GM-CSF and TNF-alpha induce phosphorylation of Ser345 on p47phox, a cytosolic component of NADPH oxidase, in human neutrophils. As Ser345 is located in the MAPK consensus sequence, we tested the effects of MAPK inhibitors. Inhibitors of the ERK1/2 pathway abrogated GM-CSF-induced phosphorylation of Ser345, while p38 MAPK inhibitor abrogated TNF-alpha-induced phosphorylation of Ser345. Transfection of HL-60 cells with a mutated p47phox (S345A) inhibited GM-CSF- and TNF-alpha-induced priming of ROS production. This event was also inhibited in neutrophils by a cell-permeable peptide containing a TAT-p47phox-Ser345 sequence. Furthermore, ROS generation, p47phox-Ser345 phosphorylation, and ERK1/2 and p38 MAPK phosphorylation were increased in synovial neutrophils from rheumatoid arthritis (RA) patients, and TAT-Ser345 peptide inhibited ROS production by these primed neutrophils. This study therefore identifies convergent MAPK pathways on Ser345 that are involved in GM-CSF- and TNF-alpha-induced priming of neutrophils and are activated in RA. Inhibition of the point of convergence of these pathways might serve as a novel antiinflammatory strategy.
15861340 Type III cryoglobulinemia complicated by renal cortical necrosis. 2005 May Renal involvement is rare in patients with type III cryoglobulinemia. We report a case of renal cortical necrosis in a patient with type III cryoglobulinemia. Renal function improved partially after treatment with plasma exchange, steroids, and cyclophosphamide. Renal magnetic resonance imaging was a valuable tool in the evaluation of the extent of renal cortical necrosis and improvement in renal vascularization after treatment.
15684417 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthrit 2005 Apr 22 A hallmark of rheumatoid arthritis (RA) is the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLSs), and the RA FLS has therefore been proposed as a therapeutic target. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been described as a pro-apoptotic factor on RA FLSs and, therefore, suggested as a potential drug. Here we report that exposure to TRAIL-induced apoptosis in a portion (up to 30%) of RA FLSs within the first 24 h. In the cells that survived, TRAIL induced RA FLS proliferation in a dose-dependent manner, with maximal proliferation observed at 0.25 nm. This was blocked by a neutralizing anti-TRAIL antibody. RA FLSs were found to express constitutively TRAIL receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) on the cell surface. TRAIL-R2 appears to be the main mediator of TRAIL-induced stimulation, as RA FLS proliferation induced by an agonistic anti-TRAIL-R2 antibody was comparable with that induced by TRAIL. TRAIL activated the mitogen-activated protein kinases ERK and p38, as well as the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway with kinetics similar to those of TNF-alpha. Moreover, TRAIL-induced RA FLS proliferation was inhibited by the protein kinase inhibitors PD98059, SB203580, and LY294002, confirming the involvement of the ERK, p38, and PI3 kinase/Akt signaling pathways. This dual functionality of TRAIL in stimulating apoptosis and proliferation has important implications for its use in the treatment of RA.
16774691 Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts. 2006 Statins, competitive inhibitors of hydroxymethylglutaryl-CoA reductase, have recently been shown to have a therapeutic effect in rheumatoid arthritis (RA). In RA, synovial fibroblasts in the synovial lining, are believed to be particularly important in the pathogenesis of disease because they recruit leukocytes into the synovium and secrete angiogenesis-promoting molecules and proteases that degrade extracellular matrix. In this study, we show a marked reduction in RA synovial fibroblast survival through the induction of apoptosis when the cells were cultured with statins. Simvastatin was more effective in RA synovial fibroblasts than atorvastatin, and both statins were more potent on tumor necrosis factor-alpha-induced cells. In contrast, in osteoarthritis synovial fibroblasts, neither the statin nor the activation state of the cell contributed to the efficacy of apoptosis induction. Viability of statin-treated cells could be rescued by geranylgeraniol but not by farnesol, suggesting a requirement for a geranylgeranylated protein for synovial fibroblast survival. Phase partitioning experiments confirmed that in the presence of statin, geranylgeranylated proteins are redistributed to the cytoplasm. siRNA experiments demonstrated a role for Rac1 in synovial fibroblast survival. Western blotting showed that the activated phosphorylated form of Akt, a protein previously implicated in RA synovial fibroblast survival, was decreased by about 75%. The results presented in this study lend further support to the importance of elevated pAkt levels to RA synovial fibroblast survival and suggest that statins might have a beneficial role in reducing the aberrant pAkt levels in patients with RA. The results may also partly explain the therapeutic effect of atorvastatin in patients with RA.
16402107 The attraction of chemokines as a target for specific anti-inflammatory therapy. 2006 Jan Since the identification of the first chemotactic cytokines 20 years ago, the field has mushroomed, with the discovery of approximately 40 ligands, which interact with 20 different cell surface receptors. At the time of writing this review, a PubMed trawl using the word 'chemokine' will recover over 28,000 manuscripts. In this article, we will give a short history of the discovery of chemokines and provide examples of the potential for therapeutic targeting of the chemokine network in inflammatory disease.