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1.
van den Berg WB 《Arthritis research》2001,3(1):18-26
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are considered to be master cytokines in chronic, destructive arthritis. Therapeutic approaches in rheumatoid arthritis (RA) patients have so far focused mainly on TNF, which is a major inflammatory mediator in RA and a potent inducer of IL-1; anti-TNF therapy shows great efficacy in RA patients. However, it is not effective in all patients, nor does it fully control the arthritic process in affected joints of good responders. Directed therapy for IL-1, with IL-1 receptor antagonist, mainly reduces erosions and is marginally anti-inflammatory. It is as yet unclear whether the limited effect is akin to the RA process or linked to suboptimal blocking of IL-1. Analysis of cytokine patterns in early synovial biopsies of RA patients reveals a marked heterogeneity, with variable staining of TNF and IL-1 beta, indicative of TNF-independent IL-1 production in at least some patients. Evidence for this pathway emerged from experimental arthritises in rodents, and is summarized in this review. If elements of the models apply to the arthritic process in RA patients, it is necessary to block IL-1 beta in addition to TNF. 相似文献
2.
Danielle Burger 《Arthritis research & therapy》2000,2(6):472-5
The intricate interactions that regulate relationships between endogenous tissue cells and infiltrating immune cells in the rheumatic joint, particularly in rheumatoid arthritis (RA), were the subject of the meeting. A better understanding of these interactions might help to define intervention points that could be used to develop specific therapies. The presentations and discussions highlighted the fact that, once chronic inflammation is established, several pro-inflammatory loops involving tumour necrosis factor (TNF)-α and interleukin (IL)-1β can be defined. Direct cellular contact with stimulated T lymphocytes induces TNF-α and IL-1β in monocytes which in turn induce functions in fibroblast-like synoviocytes. The latter include the production of stromal cell-derived factor-1α (SDF-1α) which enhances the expression of CD40L in T cells, which stimulates SDF-1α production in synoviocytes, which in turn protects T and B cells from apoptosis and enhances cell recruitment thus favoring inflammatory processes. IL-1β and TNF-α also induce IL-15 in fibroblast-like synoviocytes, which induces the production of IL-17 which in turn potentiates IL-1β and TNF-α production in monocyte-macrophages. This underlines the importance of TNF-α and IL-1β in RA pathogenesis, and helps explain the efficiency of agents blocking the activity of these cytokines in RA. Factors able to block the induction of cytokine production (such as apolipoprotein A-I [apo A-I] and interferon [IFN]-β) might interfere more distally in the inflammatory process. Furthermore, stimulated T lymphocytes produce osteoclast differentiation factor (ODF), which triggers erosive functions of osteoclasts. Therefore, factors capable of affecting the level of T lymphocyte activation, such as IFN-β, IL-15 antagonist, or SDF-1α antagonist, might be of interest in RA therapy. 相似文献
3.
4.
The antibody-mediated targeted delivery of cytokines to sites of disease is a promising avenue for cancer therapy, but it
is largely unexplored for the treatment of chronic inflammatory conditions. Using both radioactive and fluorescent techniques,
the human monoclonal antibodies L19 and G11 (specific to two markers of angiogenesis that are virtually undetectable in normal
adult tissues) were found to selectively localize at arthritic sites in the murine collagen-induced model of rheumatoid arthritis
following intravenous (i.v.) administration. The same animal model was used to study the therapeutic action of the L19 antibody
fused to the cytokines IL-2, tumour necrosis factor (TNF) and IL-10. Whereas L19–IL-2 and L19–TNF treatment led to increased
arthritic scores and paw swellings, the fusion protein L19–IL-10 displayed a therapeutic activity, which was superior to the
activity of IL-10 fused to an antibody of irrelevant specificity in the mouse. The anti-inflammatory cytokine IL-10 has been
investigated for the treatment of patients with rheumatoid arthritis, but clinical development plans have been discontinued
because of a lack of efficacy. Because the antigen recognised by L19 is strongly expressed at sites of arthritis in humans
and identical in both mice and humans, it suggests that the fusion protein L19–IL-10 might help overcome some of the clinical
limitations of IL-10 and provide a therapeutic benefit to patients with chronic inflammatory disorders, including arthritis. 相似文献
5.
《Cell cycle (Georgetown, Tex.)》2013,12(10):1539-1543
c-Fos/AP-1 controls the expression of inflammatory cytokines and matrix-degrading matrix metalloproteinases (MMPs) important in arthritis via promoter AP-1 binding motif. Among inflammatory cytokines, IL-1β is the most important inducer of a variety of MMPs, and mainly responsible for cartilage breakdown and osteoclastogenesis. IL-1β and c-Fos/AP-1 influence each other’s gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, where TNFα can act synergistically with them. While how to stop the degradation of bone and cartilage, i.e., to control MMP, has long been the central issue in the research of rheumatoid arthritis (RA), selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction. Thus, the blockade of IL-1β and/or c-Fos/AP-1 can be promising as an effective therapy for rheumatoid joint destruction in addition to the currently available TNFα blocking agents that act mainly on arthritis. 相似文献
6.
Wähämaa H Schierbeck H Hreggvidsdottir HS Palmblad K Aveberger AC Andersson U Harris HE 《Arthritis research & therapy》2011,13(4):R136
Introduction
In addition to its direct proinflammatory activity, extracellular high mobility group box protein 1 (HMGB1) can strongly enhance the cytokine response evoked by other proinflammatory molecules, such as lipopolysaccharide (LPS), CpG-DNA and IL-1β, through the formation of complexes. Extracellular HMGB1 is abundant in arthritic joint tissue where it is suggested to promote inflammation as intra-articular injections of HMGB1 induce synovitis in mice and HMGB1 neutralizing therapy suppresses development of experimental arthritis. The aim of this study was to determine whether HMGB1 in complex with LPS, interleukin (IL)-1α or IL-1β has enhancing effects on the production of proinflammatory mediators by rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). Furthermore, we examined the toll-like receptor (TLR) 4 and IL-1RI requirement for the cytokine-enhancing effects of the investigated HMGB1-ligand complexes. 相似文献7.
Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes.
High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however,
IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been
observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-α, IL-1, and receptor activator
of NF-κB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-α in inducing cytokine expression and joint
damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17
has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17
cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which
elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy. 相似文献
8.
Sander W Tas Margriet J Vervoordeldonk Najat Hajji Michael J May Sankar Ghosh Paul P Tak 《Arthritis research & therapy》2006,8(4):R86-9
Nuclear factor (NF)-κB is a key regulator of synovial inflammation. We investigated the effect of local NF-κB inhibition in
rat adjuvant arthritis (AA), using the specific IκB kinase (IKK)-β blocking NF-κB essential modulator-binding domain (NBD)
peptide. The effects of the NBD peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as rheumatoid
arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD peptide on RA FLS
in vitro. Subsequently, NBD peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease.
The severity of arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for
routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD peptides, and cytokine production was measured in the supernatant by enzyme-linked immunosorbent
assay. The NBD peptide blocked interleukin (IL)-1-β-induced IκBα phosphorylation and IL-6 production in RA FLS. Intra-articular
injection of the NBD peptide led to significantly reduced severity of arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of tumor necrosis factor (TNF)-α
and IL-1-β in the synovium. Incubation of human macrophages with NBD peptides resulted in 50% inhibition of IL-1-β-induced
TNF-α production in the supernatant (p < 0.01). In addition, the NBD peptide decreased TNF-α-induced IL-6 production by human RA synovial tissue biopsies by approximately
42% (p < 0.01). Specific NF-κB blockade using a small peptide inhibitor of IKK-β has anti-inflammatory effects in AA and human RA
synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate
that IKK-β-targeted NF-κB blockade using the NBD peptide could offer a new approach for the local treatment of arthritis. 相似文献
9.
Judith van Holten Kris Reedquist Pascale Sattonet-Roche Tom JM Smeets Christine Plater-Zyberk Margriet J Vervoordeldonk Paul P Tak 《Arthritis research & therapy》2004,6(3):R239
We investigated the therapeutic potential and mechanism of action of IFN-β protein for the treatment of rheumatoid arthritis
(RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections
of recombinant mouse IFN-β or saline for 7 days. Disease progression was monitored by visual clinical scoring and measurement
of paw swelling. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis. Proteoglycan
depletion was determined by safranin O staining. Expression of cytokines, receptor activator of NF-κB ligand, and c-Fos was
evaluated immunohistochemically. The IL-1-induced expression of IL-6, IL-8, and granulocyte/macrophage-colony-stimulating
factor (GM-CSF) was studied by ELISA in supernatant of RA and osteoarthritis fibroblast-like synoviocytes incubated with IFN-β.
We also examined the effect of IFN-β on NF-κB activity. IFN-β, at 0.25 μg/injection and higher, significantly reduced disease
severity in two experiments, each using 8–10 mice per treatment group. IFN-β-treated animals displayed significantly less
cartilage and bone destruction than controls, paralleled by a decreased number of positive cells of two gene products required
for osteoclastogenesis, receptor activator of NF-κB ligand and c-Fos. Tumor necrosis factor α and IL-6 expression were significantly
reduced, while IL-10 production was increased after IFN-β treatment. IFN-β reduced expression of IL-6, IL-8, and GM-CSF in
RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-κB activity. The data support the view that
IFN-β is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation. 相似文献
10.
Fionula M Brennan 《Arthritis research & therapy》2001,3(4):211-213
In recent years, the effectiveness of anti-TNF therapy in treating rheumatoid arthritis (RA) has become apparent. While trials of IL-1 receptor antagonist in RA have been encouraging, it clearly is more difficult to target two molecules (IL-1 α and β) than one (TNF-α). In his review article, Professor Wim van den Berg argues that both TNF-α and IL-1 must be blocked in RA and that although TNF is clearly a potent inflammatory molecule, the dominant cytokine in the subsequent degradation of the joint tissue is IL-1. This commentary discusses his hypothesis in light of animal studies and the limitations of the conclusions that can be drawn from them. More broadly, it discusses the biology of TNF-α and IL-1 and suggests explanations of why TNF-α is a pivotal cytokine in this disease. 相似文献
11.
Yves Chicheportiche Rachel Chicheportiche Irene Sizing Jeff Thompson Christopher B Benjamin Christine Ambrose Jean-Michel Dayer 《Arthritis research & therapy》2001,4(2):126-8
Human tumour necrosis factor (TNF)-like weak inducer of apoptosis (hTWEAK) and two anti-hTWEAK mAbs were tested for their ability to elicit or block inflammatory responses in cultured human dermal fibroblasts and synoviocytes. Incubation with hTWEAK increased the production of prostaglandin E2, matrix metalloproteinase-1 (MMP-1), IL-6, and the chemokines IL-8, RANTES (regulated on activation, normal T expressed and secreted) and interferon-γ-inducible protein-10 (IP-10) in culture supernatant of fibroblasts and synoviocytes. In combination with TNF or IL-1β, hTWEAK further stimulated the secretion of prostaglandin E2, MMP-1, IL-6 and IL-8 up to fourfold, and IP-10 and RANTES up to 70-fold compared to TNF or IL-1β alone. An anti-hTWEAK mAb, BCB10, blocked the effects of hTWEAK, whereas hTWEAK crosslinked by the anti-hTWEAK mAb, BEB3, further stimulated the inflammatory response of fibroblasts and synoviocytes. The anti-hTWEAK mAbs were ineffective in blocking or increasing the responses of TNF or IL-1β and blocking anti-TNF mAb was ineffective in preventing the responses to TWEAK. These results were also confirmed at the RNA level for MMP-1, macrophage chemoattractant protein-1, RANTES, macrophage inflammatory protein-1α, IP-10 and IL-8. TWEAK in synergism with IL-1 and TNF may be an additional cytokine that plays a role in destructive chronic arthritic diseases. 相似文献
12.
Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes. High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however, IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-alpha, IL-1, and receptor activator of NF-kappaB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17 has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy. 相似文献
13.
Ceccarelli F Perricone C Fabris M Alessandri C Iagnocco A Fabro C Pontarini E De Vita S Valesini G 《Arthritis research & therapy》2011,13(4):R111
Introduction
Single nucleotide polymorphisms (SNPs) of transforming growth factor β (TGF-β) and IL-6 genes (respectively, 869C/T and -174G/C) have been associated with radiographic severity of bone-erosive damage in patients with rheumatoid arthritis (RA). Musculoskeletal ultrasound (US) is more sensitive than radiography in detecting bone erosion. We analyzed the association between TGF-β 869C/T and IL-6 -174G/C SNPs and bone-erosive damage, evaluated by US, in a cohort of patients with severely active RA. 相似文献14.
Isidoro González-Álvaro Carmen Domínguez-Jiménez Ana M Ortiz Vanessa Núñez-González Pedro Roda-Navarro Elena Fernández-Ruiz David Sancho Francisco Sánchez-Madrid 《Arthritis research & therapy》2006,8(4):R88-11
We have characterized the lymphocyte subset and the receptor molecules involved in inducing the secretion of TNF by monocytic
cells in vitro. The TNF secreted by monocytic cells was measured when they were co-cultured with either resting or IL-15-stimulated lymphocytes,
T cells, B cells or natural killer (NK) cells isolated from the peripheral blood of healthy subjects and from the synovial
fluid from patients with inflammatory arthropathies. Co-culture with IL-15-activated peripheral blood or synovial fluid lymphocytes
induced TNF production by monocytic cells within 24 hours, an effect that was mainly mediated by NK cells. In turn, monocytic
cells induced CD69 expression and IFN-γ production in NK cells, an effect that was mediated mainly by β2 integrins and membrane-bound IL-15. Furthermore, IFN-γ increased the production of membrane-bound IL-15 in monocytic cells.
Blockade of β2 integrins and membrane-bound IL-15 inhibited TNF production, whereas TNF synthesis increased in the presence of anti-CD48
and anti-CD244 (2B4) monoclonal antibodies. All these findings suggest that the cross-talk between NK cells and monocytes
results in the sustained stimulation of TNF production. This phenomenon might be important in the pathogenesis of conditions
such as rheumatoid arthritis in which the synthesis of TNF is enhanced. 相似文献
15.
Onno J Arntz Jeroen Geurts Sharon Veenbergen Miranda B Bennink Ben T van den Brand Shahla Abdollahi-Roodsaz Wim B van den Berg Fons A van de Loo 《Arthritis research & therapy》2010,12(2):R61
Introduction
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that mainly affects synovial joints. Biologics directed against tumor-necrosis-factor (TNF)-α are efficacious in the treatment of RA. However, the role of TNF receptor-1 (TNFR1) in mediating the TNFα effects in RA has not been elucidated and conflicting data exist in experimental arthritis models. The objective is to investigate the role of TNFR1 in the synovial lining cells (SLC) and the reticuloendothelial system (RES) during experimental arthritis. 相似文献16.
17.
Andrew M. Jackson Anton B. Alexandrov S. Prescott Keith James 《Cancer immunology, immunotherapy : CII》1995,40(2):119-124
Intravesical immunotherapy for bladder cancer is the most effective form of tumour immunotherapy. Following repeated instillations
of bacillus Calmette-Guérin (BCG) organisms into the bladder large 0quantities of several cytokines are detected in the urine.
These cytokines include interleukins IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor α (TNFα), interferon γ (IFNγ)
and also soluble intercellular adhesion molecule ICAM-1. In the work reported here we simultaneously quantified urinary levels
of TNFα, TNFβ, TNF receptor I and TNF receptor II by enzyme-linked immunosorbent assay (ELISA) techniques and compared this
with bioactive levels of TNF. This was undertaken with a limited number of patients throughout a course of six instillations
of immuno therapy. Sequential instillations of BCG induced secretion of TNFα and TNFβ into urine. These cytokines were not
always secreted simultaneously, perhaps suggesting differential regulation of their synthesis. Maximal concentrations of TNFα
were 675 pg/ml and TNFβ 47 pg/ml. High levels of both species of soluble TNF receptor were readily identified in urine. Maximal
levels of sTNF-RI were 6200 pg/ml (range from 0) and for sTNF-RII 7800 pg/ml (range from 0). Contrasting with earlier published
observations concerning cytokine levels, the concentration of soluble receptor did not increase with repeated instillation.
In apparent contrast with the ELISA data, very low levels of bioactive TNF were identified by the L929 bioassay (maximum concentration
1 U/ml) despite the elevated concen t ration of immunoreactive TNF. The large concentrations of soluble TNF receptor in patients’
urine samples could account for the apparently low bioactivity as determined by the L929 cytotoxicity assay. The precise nature
of the role of TNF in BCG immunotherapy remains undetermined; however, it is thought that proinflammatory cytokines are in
part responsible for the clinical efficacy of this therapeutic approach. Whether other cytokines are antogonised by soluble
binding proteins remains to be determined. Furthermore, whether TNF is bioactive in the bladder wall and only neutralised
in the urine also requires investigation.
Received: 24 August 1994 / Accepted: 17 October 1994 相似文献
18.
Bone destruction is a frequent and clinically serious event in patients with rheumatoid arthritis (RA). Local joint destruction
can cause joint instability and often necessitates reconstructive or replacement surgery. Moreover, inflammation-induced systemic
bone loss is associated with an increased fracture risk. Bone resorption is a well-controlled process that is dependent on
the differentiation of monocytes to bone-resorbing osteoclasts. Infiltrating as well as resident synovial cells, such as T
cells, monocytes and synovial fibroblasts, have been identified as sources of osteoclast differentiation signals in RA patients.
Pro-inflammatory cytokines are amongst the most important mechanisms driving this process. In particular, macrophage colony-stimulating
factor, RANKL, TNF, IL-1 and IL-17 may play dominant roles in the pathogenesis of arthritis-associated bone loss. These cytokines
activate different intracellular pathways to initiate osteoclast differentiation. Thus, over the past years several promising
targets for the treatment of arthritic bone destruction have been defined. 相似文献
19.
Bramlage CP Häupl T Kaps C Ungethüm U Krenn V Pruss A Müller GA Strutz F Burmester GR 《Arthritis research & therapy》2006,8(3):R58-10
Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the
development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in
synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis
(OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression
of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation,
by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1β, TNF-α, stromelysin and collagenase I in synovial
tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA
in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed
tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less
pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial
tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed
in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact
of these factors on homeostasis and remodeling in joint physiology and pathology. 相似文献