Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-1 molecules are encoded by two distinct genes, IL-1alpha and IL-1beta. Both isoforms possess essentially identical activities and potencies, whereas IL-1alpha, in contrast to IL-1beta, is known to act as a membrane-associated IL-1 (MA-IL-1) and plays an important role in a variety of inflammatory situations. The transgenic (Tg) mouse line (Tg1706), which was generated in our laboratory, overexpresses human IL-1alpha (hIL-1alpha) and exhibits a severe arthritic phenotype characterized by autonomous synovial proliferation with subsequent cartilage destruction. Because the transgene encoded Lys(64) to Ala(271) of the hIL-1alpha amino acid sequence, Tg mice may overproduce MA-IL-1 as well as soluble IL-1alpha. The present study investigated whether MA-IL-1 contributes to synovial proliferation and cartilage destruction in the development of arthritis. Flow cytometric analysis revealed that both macrophage-like and fibroblast-like synoviocytes constitutively produce MA-IL-1. D10 cell proliferation assay revealed MA-IL-1 bioactivity of paraformaldehyde-fixed synoviocytes and the further induction of endogenous mouse MA-IL-1 via autocrine mechanisms. MA-IL-1 expressed on synoviocytes triggered synoviocyte self-proliferation through cell-to-cell (i.e., juxtacrine) interactions and also promoted proteoglycan release from the cartilage matrix in chondrocyte monolayer culture. Interestingly, the severity of arthritis was significantly correlated with MA-IL-1 activity rather than with soluble IL-1alpha activity or concentration of serum hIL-1alpha. Moreover, when the Tg1706 line was compared with the Tg101 line, which selectively overexpresses the 17-kDa mature hIL-1alpha, the severity of arthritis was significantly higher in the Tg1706 line than in the Tg101 line. These results suggest that MA-IL-1 contributes to synoviocyte self-proliferation and subsequent cartilage destruction in inflammatory joint disease such as rheumatoid arthritis.
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PMID:Membrane-associated IL-1 contributes to chronic synovitis and cartilage destruction in human IL-1 alpha transgenic mice. 1468 69

Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.
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PMID:Thalidomide induces apoptosis in human monocytes by using a cytochrome c-dependent pathway. 1506 94

The transcription factor activator protein-1 (AP-1) is an attractive target for the treatment of immunoinflammatory diseases, such as rheumatoid arthritis. Using the three-dimensional (3D) X-ray crystallographic structure of the DNA-bound basic region leucine zipper (bZIP) domains of AP-1, new cyclic disulfide decapeptides were designed and synthesized that demonstrated AP-1 inhibitory activities. The most potent inhibition was exhibited by Ac-c[Cys-Gly-Gln-Leu-Asp-Leu-Ala-Asp-Gly-Cys]-NH2 (peptide 2) (IC50 = 8 microM), which was largely due to the side chains of residues 3-6 and 8 of the peptide, as shown by an alanine scan. To provide structural information about the biologically active conformation of peptide 2, the structures of peptide 2 derived from molecular dynamics simulation of the bZIP-peptide 2 complex with explicit water molecules were superimposed on the solution structures derived from NMR measurements of peptide 2 in water. These showed a strong structural similarity in the backbones of residues 3-7 and enabled the construction of a 3D pharmacophore model of AP-1 binding compounds, based on the chemical and structural features of the amino acid side chains of residues 3-7 in peptide 2.
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PMID:Design, synthesis, and biological evaluation of new cyclic disulfide decapeptides that inhibit the binding of AP-1 to DNA. 1529 95

Tumor necrosis factor (TNF) antagonism with monoclonal antibodies is an effective therapy for severe Crohn's disease and rheumatoid arthritis. Recent studies have suggested that induction of apoptosis of inflammatory cells contributes to this therapeutic effect. We investigated whether infliximab (a mouse-human IgG1 chimeric anti-TNF monoclonal antibody) could induce apoptosis in vivo in human-mouse chimeras, created by reconstitution of severe combined immunodeficiency/beige mice with THP-1 (human monocytic cell line) or Jurkat cells (human T cell line). Infliximab treatment of chimeric mice depleted spleen and peritoneum from THP-1 cells and Jurkat cells and decreased production of the human cytokines IL-10 and IL-12 in vivo. Cell death was shown to occur already within 1 h of treatment. Infliximab effects were independent of FcgammaR binding or complement activation. Cell death resulted from apoptosis induction in a caspase-dependent pathway, as evidenced by the in vitro protective effect of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone (Z-VAD-FMK). These data provide support for caspase-dependent apoptosis induction being the mechanism of action of infliximab in vivo.
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PMID:Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. 1589 92

A non-glycosaminoglycan (GAG)-binding variant of the pleiotropic chemokine CCL7 was generated by mutating to alanine the basic (B) amino acids within an identified (44)BXBXXB(49) GAG-binding motif. Unlike wild-type (wt) CCL7, the mutant sequence had no affinity for heparin. However, the mutant retained a normal affinity for CCR1, CCR2b, and CCR3, and produced a normal calcium flux in mononuclear leukocytes. Both the wt and mutant proteins elicited an equal leukocyte chemotactic response within a solute diffusion gradient but, unlike the wt protein, the mutant failed to stimulate cell migration across a model endothelium. The number of leukocytes recruited to murine air pouches by the mutant sequence was lower than that recruited by wt CCL7. Furthermore, the presence of a mixture of a mutant and wt CCL7 within the air pouch elicited no significant cell accumulation. Cell recruitment also failed using a receptor-sharing mixture of mutant CCL7 and wt CCL5 or a nonreceptor sharing mixture of mutant CCL7 and wt CXCL12. The potential of the mutant sequence to modulate inflammation was confirmed by demonstration of its ability to inhibit the chemotactic response generated in vitro by synovial fluid from patients with active rheumatoid arthritis. A further series of experiments suggested that the non-GAG-binding mutant protein could potentially induce receptor desensitization before, and at a site remote from, any physiological recognition of GAG-bound chemokines. These data demonstrate that GAG binding is required for chemokine-driven inflammation in vivo and also suggest that a non-GAG-binding chemokine receptor agonist can inhibit the normal vectorial leukocyte migration mediated by chemokines.
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PMID:A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation. 1600 30

IL-10 is a Th2 cytokine important for inhibiting cell-mediated immunity while promoting humoral responses. Human IL-10 (hIL-10) has anti-inflammatory, immunosuppressive as well as immunostimulatory characteristics, whereas viral IL-10 (vIL-10), a homologue of hIL-10 encoded by Epstein Barr virus (EBV), lacks several immunostimulatory functions. The immunostimulatory characteristic of hIL-10 has been attributed to a single amino acid, isoleucine at position 87, which in vIL-10 is alanine. A mutant hIL-10 in which isoleucine has been substituted (mut.hIL-10) is biologically active with only immunosuppressive, but not immunostimulatory, functions, making it a potentially superior therapeutic for inflammatory diseases. To compare the efficacy of mut.hIL-10 with hIL-10 and vIL-10 in blocking the progression of rheumatoid arthritis, we used replication defective adenoviral vectors to deliver intra-articularly the gene encoding hIL-10, vIL-10 or mut.hIL-10 to antigen-induced arthritic (AIA) knee joints in rabbits. Intra-articular expression of hIL-10, vIL-10, and mut.hIL-10 resulted in significant improvement of the pathology in the treated joints to similar levels. These observed changes included a significant reduction in intra-articular leukocytosis and the degree of synovitis, as well as normalization of cartilage matrix metabolism. Our results suggest that hIL-10, vIL-10, and mut.hIL-10 are all equally therapeutic in the rabbit AIA model for treating disease pathology.
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PMID:Human, viral or mutant human IL-10 expressed after local adenovirus-mediated gene transfer are equally effective in ameliorating disease pathology in a rabbit knee model of antigen-induced arthritis. 1670 45

Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule Aq. T-cell recognition of a peptide from type II collagen, CII256-270, bound to Aq is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of CII256-270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a beta-D-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells.
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PMID:Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis. 1676 55

Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in diarthrodial joints. We have previously established that mice transgenic for the human DR genes associated with RA are susceptible to collagen-induced arthritis (CIA) and we have identified a determinant of type II collagen (CII(263-270)) that triggers T-cell immune responses in these mice. We have also determined that an analog of CII(263-270) would suppress disease in DR1 transgenic mice. Because the immunodominant determinant is the same for both DR1 transgenic and DR4 transgenic mice, we attempted to determine whether the analog peptide that was suppressive in DR1 transgenic mice would also be effective in suppressing CIA in DR4 transgenic mice. We treated DR4 transgenic mice with two analog peptides of CII that contained substitutions in the core of the immunodominant determinant: CII(256-276) (F263N, E266D) and CII(256-270) (F263N, E266A). Mice were observed for CIA, and T-cell proliferative responses were determined. Either peptide administered at the time of immunization with CII significantly downregulated arthritis. Binding studies demonstrated that replacement of the phenylalanine residue in position 263 of the CII peptide with asparagine significantly decreased the affinity of the peptide for the DR4 molecule. In contrast, replacement of the glutamic acid residue in position 266 with aspartic acid or with alanine had differing results. Aspartic acid reduced the affinity (35-fold) whereas alanine did not. Both peptides were capable of suppressing CIA. With the use of either peptide, CII(256-276) (F263N, E266D) or CII(256-270) (F263N, E266A), the modulation of CIA was associated with an increase in T-cell secretion of IL-4 together with a decrease in IFN-gamma. We have identified two analog peptides that are potent suppressors of CIA in DR4 transgenic mice. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of HLA-DR4 that can suppress autoimmune arthritis.
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PMID:Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice. 1698 3

Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100 microg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3-v10) only at a relatively high concentration (200 microg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific.
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PMID:Expression of extra trinucleotide in CD44 variant of rheumatoid arthritis patients allows generation of disease-specific monoclonal antibody. 1738 58

Numerous associations have been documented between the Epstein-Barr virus (EBV) and rheumatoid arthritis (RA). Thus, anti-EBV antibody titers are higher in RA patients than in healthy controls. Lymphocytes from RA patients show impaired responses to EBV. Several EBV antigens share similarities with self antigens; more specifically, the glycine/alanine repeats in EBNA-1 resemble synovial proteins and the EBV gp110 glycoprotein contains a copy of the shared epitope. Cell-mediated responses to EBV replicative cycle proteins and to gp110 have been documented in joint fluid from RA patients. In situ hybridization and PCR techniques have identified EBV antigens and genetic material within the rheumatoid synovium, albeit with variable yields. The EBV burden in peripheral blood mononuclear cells is higher in RA patients than in controls. EBNA-1 can undergo citrullination, and the EBV can induce antibodies to citrullinated peptides. RA patients are at increased risk for lymphoma, including EBV-associated lymphoma. Despite these multiple and complex links between EBV and RA, proof of a causal association is lacking. EBV infection may contribute indirectly to the pathophysiology of RA by impairing immune control of EBV replication, causing increased exposure to EBV antigens and, thereby, chronic inflammation. The effect of biotherapies for RA on EBV-host relations needs to be investigated.
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PMID:Pathophysiological links between rheumatoid arthritis and the Epstein-Barr virus: an update. 1856 35


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