Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DBA/1LacJ mice were immunized with type II collagen and boosted with bacterial lipopolysaccharide (LPS) 17 days later to induce accelerated arthritis. Clinical signs of inflammation were observed as early as Day 20. Matrix metalloproteinases MMP-2, -3, -9, and -13, but not MMP-12, mRNA levels were increased on Day 24. Administration of anti-VLA-4 antibody (mAb; 8 mg/kg/day for 3 days) at the time of LPS treatment strikingly inhibited arthritis-induced paw inflammation and histological scores, but not the increase in MMP expression. A higher dose of mAb (20 mg/kg/day for 4 days) inhibited pathology and normalized the levels of MMP mRNAs. In conclusion, the pathophysiology of this accelerated model of arthritis is VLA-4-dependent, and VLA-4-mediated events have a role in inflammation-induced MMP expression. Inhibition of arthritis-induced increases in MMP expression is not necessary to reduce pathology. This model is well suited for identifying agents that block integrin VLA-4 in vivo.
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PMID:Blockade of integrin VLA-4 prevents inflammation and matrix metalloproteinase expression in a murine model of accelerated collagen-induced arthritis. 1279 50

The control point by which chondrocytes take the decision between the cartilage differentiation program or the joint formation program is unknown. Here, we have investigated the effect of alpha5beta1 integrin inhibitors and bone morphogenetic protein (BMP) on joint formation. Blocking of alpha5beta1 integrin by specific antibodies or RGD peptide (arginine-glycine-aspartic acid) induced inhibition of pre-hypertrophic chondrocyte differentiation and ectopic joint formation between proliferating chondrocytes and hypertrophic chondrocytes. Ectopic joint expressed Wnt14, Gdf5, chordin, autotaxin, type I collagen and CD44, while expression of Indian hedgehog and type II collagen was downregulated in cartilage. Expression of these interzone markers confirmed that the new structure is a new joint being formed. In the presence of BMP7, inhibition of alpha5beta1 integrin function still induced the formation of the ectopic joint between proliferating chondrocytes and hypertrophic chondrocytes. By contrast, misexpression of alpha5beta1 integrin resulted in fusion of joints and formation of pre-hypertrophic chondrocytes. These facts indicate that the decision of which cell fate to make pre-joint or pre-hypertrophic is made on the basis of the presence or absence of alpha5beta1 integrin on chondrocytes.
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PMID:Coordination of chondrocyte differentiation and joint formation by alpha5beta1 integrin in the developing appendicular skeleton. 1532 44

Collagen-induced arthritis was evoked by an injection of lipopolysaccharide and anti-type II collagen antibody in mice. In parallel with the onset of arthritis, granulocytes with large light scatter and a Mac-1(+) Gr-1(+) phenotype expanded in the joints of these mice. Lymphocytes with a CD3(-) B220(+) phenotype (i.e. B220(+) B cells) were the major population among lymphocyte subsets in the joints, irrespective of disease. To determine the origin of these leucocyte populations in the joints and other organs, parabiotic experiments using CBF(1)Ly5.1 and CBF(1)Ly5.2 mice were conducted in mice with and without collagen-induced arthritis. As expected, leucocyte populations in the liver and spleen became a half-and-half mixture of their own cells and partner cells (e.g. approximately 45% of Ly5.1(+) cells in Ly5.2(+) partner mice). However, such a mixture was extremely delayed in the joints and bone marrow, even in mice with arthritis. These results suggest that, because circulatory blood is not exchanged in the joints, granulocytes and other lymphocytes are generated in situ in the inflamed joints of mice with collagen-induced arthritis or are possibly supplied by the bone marrow. It is of interest that granulocytes in the joints expanded, even without a supply from another site, namely, the synovium.
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PMID:No mixing of granulocytes and other lymphocytes in the inflamed joints of parabiosis mice with collagen-induced arthritis: possible in situ generation. 1560 3

alpha-Linked galactooligosaccharide (alpha-GOS) has been reported to change the composition of enteric microflora. In the present study, the antiarthritic effect of alpha-GOS was evaluated by employing adjuvant-induced arthritis (AIA) in Wistar rats and type II collagen-induced arthritis (CIA) in DBA/1J mice. The animals were given alpha-GOS orally. This substance had beneficial effects on both clinical signs, such as erythema and swelling of the limbs, and histopathological findings in the hind paw joints in a dose-dependent manner. alpha-GOS reduced the plasma nitrite/nitrate (NOx) level in rats with AIA. In the cell culture system employing peritoneal macrophages from rats with AIA, alpha-GOS enhanced interleukin-1 production without lipopolysaccharide stimulation in a dose-dependent manner, suggesting that alpha-GOS stimulates peritoneal macrophages through modulation of enteric microflora. Since alpha-GOS modulates the composition of the enteric microflora, the antiarthritic effects of alpha-GOS could be partly attributable to its immunomodulating activity. Thus, alpha-GOS is a potential functional food for the treatment of human rheumatoid arthritis.
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PMID:Effects of alpha-linked galactooligosaccharide on adjuvant-induced arthritis in Wistar rats and type II collagen-induced arthritis in DBA/1J mice. 1564 38

Mice with a disrupted gp49B gene, which encodes gp49B1 that is expressed on certain hematopoietic cells and has two immunoreceptor tyrosine-based inhibitory motifs (ITIM), exhibit augmented FcepsilonRI-initiated mast cell degranulation and resultant tissue edema. gp49B1-deficient (gp49B(-/-)) mice also exhibit exaggerated lipopolysaccharide (LPS)-induced intravascular neutrophil aggregation leading to cutaneous microangiopathy. To determine whether gp49B(-/-) mice exhibit elevated cytokine and chemokine levels leading to pathologic inflammation, we quantified clinical and morphologic parameters of arthritis and tissue levels of contributory mediators in gp49B(-/-) and gp49B1-sufficient (gp49B(+/+)) mice injected with anti-type II collagen monoclonal antibody (mAb) and LPS. Clinical scores for joint swelling and histological assessments of synovial thickness and cartilage matrix depletion at day 7 were significantly 2.3- to 2.5-fold greater and were more prolonged in gp49B(-/-) mice. At day 5, the amounts of IL-1beta, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 were 2.1-, 2.5-, and 12-fold greater in joint extracts from gp49B(-/-) mice. A significant 2.7-fold more neutrophils infiltrated the synovium of gp49B(-/-) mice at day 7, and neutrophilia persisted with the delayed resolution of the synovitis. mAb-mediated depletion of neutrophils prevented the synovitis in both strains. Thus, gp49B1 counter-regulates the cytokine and chemokine induction and attendant neutrophilia that are all essential for synovitis and cartilage matrix depletion.
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PMID:gp49B1 deficiency is associated with increases in cytokine and chemokine production and severity of proliferative synovitis induced by anti-type II collagen mAb. 1582 66

Levels of HtrA1 protein in cartilage have been reported to elevate in joints of human osteoarthritis patients. To understand roles of HtrA1 in normal osteogenesis as well as in pathogenesis of arthritis, we examine HtrA1 expression pattern during bone and cartilage development and in articular cartilage affected by experimental arthritis. HtrA1 is not expressed in mesenchymal or cartilage condensations before initiation of ossification. When ossification begins in the condensations, the expression of HtrA1 starts in chondrocytes undergoing hypertrophic differentiation near the ossification center. Hypertrophic chondrocytes found in adult articular cartilage and epiphyseal growth plates also express HtrA1. When arthritis is induced by injection of anti-collagen antibodies and lipopolysaccharide, resting chondrocytes proceed to terminal hypertrophic differentiation and start expressing HtrA1. These data suggest that hypertrophic change induces HtrA1 expression in chondrocytes both in normal and pathological conditions. HtrA1 has been reported to inhibit TGF-beta signaling. We show that HtrA1 digests major components of cartilage, such as aggrecan, decorin, fibromodulin, and soluble type II collagen. HtrA1 may, therefore, promote degeneration of cartilage by inducing terminal hypertrophic chondrocyte differentiation and by digesting cartilage matrix though its TGF-beta inhibitory activity and protease activity, respectively. In bone, active cuboidal osteoblasts barely express HtrA1, but osteoblasts which flatten and adhere to the bone matrix and osteocytes embedded in bone are strongly positive for HtrA1 production. The bone matrix shows a high level of HtrA1 protein deposition akin to that of TGF-beta, suggesting a close functional interaction between TGF-beta and HtrA1.
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PMID:Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. 1599 70

THR0921 is a novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonist with potent anti-diabetic properties. Because of the proposed role of PPARgamma in inflammation, we investigated the potential of orally active THR0921 to inhibit the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by the injection of bovine type II collagen in complete Freund's adjuvant on days 0 and 21. Mice were treated with THR0921 (50 mg/kg/day) starting on the day of the booster injection and throughout the remaining study period. Both clinical disease activity scores as well as histological scores of joint destruction were significantly reduced in mice treated with THR0921 compared to untreated mice. Proliferation of isolated spleen cells, as well as circulating levels of IgG antibody to type II collagen, was decreased by THR0921. Moreover, spleen cell production of IFN-gamma, tumor necrosis factor (TNF)-alpha and IL-1beta in response to exposure to lipopolysaccharide or type II collagen was reduced by in vivo treatment with THR0921. Steady state mRNA levels of TNF-alpha, IL-1beta, monocyte chemotactic protein-1 and receptor activator of nuclear factor kappaB ligand (RANKL) in isolated joints were all decreased in mice treated with THR0921. Finally, THR0921 inhibited osteoclast differentiation of bone marrow-derived cells stimulated with macrophage colony-stimulating factor and RANKL. In conclusion, THR0921 attenuates collagen-induced arthritis in part by reducing the immune response. As such, PPARgamma may be an important therapeutic target for rheumatoid arthritis.
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PMID:THR0921, a novel peroxisome proliferator-activated receptor gamma agonist, reduces the severity of collagen-induced arthritis. 1635 94

Adenosine has anti-inflammatory activity. Adenosine deaminase (EC 3.5.4.4) metabolizes extracellular adenosine, resulting in an exacerbation of inflammation. Consequently, it was hypothesized that adenosine deaminase inhibitors produce anti-inflammatory activity by increasing extracellular adenosine concentration. This group recently developed a non-nucleoside adenosine deaminase inhibitor, FR234938, by using rational structure-based drug design. FR234938 inhibits recombinant human adenosine deaminase enzyme competitively. FR234938 inhibits interleukin (IL)-6-dependent immunoglobulin (Ig) M production by SKW6.4 cells, in the presence of adenosine. Inhibitory effect of FR234938/adenosine combination is blocked by an A2a adenosine receptor antagonist. FR234938 also inhibits anti-type II collagen delayed type hypersensitivity (DTH) in a dose-dependent manner, both in the presence and absence of recombinant human adenosine deaminase. Moreover, FR234938 inhibits tumor necrosis factor (TNF)-alpha and IL-10 production in a lipopolysaccharide (LPS)-induced cytokine production model in mice. These results indicate that FR234938 has potential anti-inflammatory activity. Non-nucleoside adenosine deaminase inhibitor FR234938 has good potential as a new type of anti-rheumatic and anti-inflammatory drug, by modulating host-defense concentrations of adenosine.
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PMID:Anti-inflammatory activity of non-nucleoside adenosine deaminase inhibitor FR234938. 1651 82

Thioredoxin (TRX) is an oxidative stress-inducible biological antioxidant that is highly expressed in the synoviocytes of rheumatoid arthritis (RA) patients. There is much evidence that oxidative stress plays a key role in the inflammation and destruction of RA joints; the functional relationship between TRX and RA remains unknown, however. We therefore investigated the role played by TRX in the inflammatory and joint-damaging processes of RA using a murine model in which arthritis was induced by administering a mixture of anti-type II collagen monoclonal antibodies (mAb) and lipopolysaccharide (LPS). In Wt mice mAb/LPS injection induced neutrophil infiltration, cartilage destruction, and chondrocyte apoptosis within the joints, all of which were dramatically suppressed in TRX transgenic (TRX-Tg) mice. Moreover, the 8-hydoxy-2'-deoxyguanosine (8-OHdG) expression seen in Wt mice after mAb/LPS injection was almost completely inhibited in TRX-Tg mice. The administration of recombinant TRX also suppressed mAb/LPS-induced joint swelling in Wt mice. Taken together, these results suggest that TRX protects against arthritis and is a plausible candidate with which to develop novel therapies for the treatment of RA.
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PMID:Thioredoxin protects against joint destruction in a murine arthritis model. 1667 11

In mice arthritis model induced by anti-type II collagen (CII) antibodies and lipopolysaccharide (LPS), most of cells that infiltrated into the joint space were neutrophils. To investigate the role of neutrophils in the pathogenesis of arthritis, we depleted the neutrophils in vivo by injection of the antibody against Gr-1 expressed mainly on neutrophils. The neutrophil depletion completely inhibited the arthritis development. Furthermore, neutrophil depletion in mice that had already developed arthritis ameliorated the disease. These results showed that neutrophils are indispensable not only for the development, but also for the maintenance of arthritis. Next, we tried to develop arthritis in C5-deficient mice to investigate the involvement of C5a, one of chemotactic factors for neutrophils. C5-deficient mice showed significant reduction in arthritis development in comparison with wild type mice. Injection of pertussis toxin (Ptx) into the mice, which inhibits the signals from the inhibitory G-protein coupled-receptors including the C5a receptor, suppressed the development of arthritis. Furthermore, Ptx also ameliorated the arthritis when injected into mice that had already developed the disease. These results suggest the important role of chemotactic factors involving C5a and inhibitory G-protein (Gi)-coupled receptors not only in the development, but also in the maintenance of arthritis.
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PMID:Essential role of neutrophils in anti-type II collagen antibody and lipopolysaccharide-induced arthritis. 1683 50


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