Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major pathologic manifestations of rheumatoid arthritis (RA) and osteoarthritis (OA) are joint inflammation and articular cartilage resorption by proinflammatory cytokine-stimulated matrix metalloproteinases (MMPs) and aggrecanases. The Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) is effective for treatment of various types of arthritis. However, mechanisms and targets of its actions are poorly understood. Anti-inflammatory activities of the extracts of this plant were previously attributed to inhibition of cyclooxygenase-2 mRNA and prostaglandin E(2) synthesis. Here, we show that in primary human femoral head osteoarthritic and normal bovine chondrocytes, TWHF partially or completely inhibited mRNA and protein expression of tumor necrosis factor-alpha, interleukin (IL)-1, and IL-17-inducible MMP-3 and MMP-13. This agent also inhibited cytokine-stimulated MMP-3 protein expression in human synovial fibroblasts. A dose range of 2.5 to 10 ng/ml of TWHF was effectively inhibitory for IL-1. Pretreatment for 30 min or 1 h (but not 2-10 h) after IL-1 treatment with TWHF inhibited MMP-3 RNA induction. The inhibitory doses had no adverse effect on the viability of chondrocytes. Mechanistic studies revealed no impact on the activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases. Instead, TWHF partially inhibited DNA binding capacity of cytokine-stimulated activating protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) transcription factors. Therefore, besides its anti-inflammatory activity, this agent may also be effective in blocking cartilage matrix resorption by MMPs by impairing AP-1 and NF-kappaB binding activities. Thus, TWHF extract contains novel inhibitors of MMP expression that may be of therapeutic potential in arthritis and other conditions associated with increased MMPs.
Mol Pharmacol 2001 May
PMID:Tripterygium wilfordii Hook F extract suppresses proinflammatory cytokine-induced expression of matrix metalloproteinase genes in articular chondrocytes by inhibiting activating protein-1 and nuclear factor-kappaB activities. 1130 4

Anti-TNF-alpha therapy has shown clear efficacy in the treatment of rheumatoid arthritis (RA). Since some patients do not respond and the treatment is suspensive, combination therapy may be of interest. Other cytokines produced by monocytes such as IL-1, IL-12, IL-18 are also involved. The secretion of these cytokines is regulated by subsets of T-lymphocytes. Among these, IL-17 producing Th1 cells appear to contribute directly to the destructive process. Furthermore, this T-cell contribution enhances the action of monocyte derived proinflammatory cytokines. Using models of human RA synovium inflammation and bone resorption, ex vivo results suggest that combination therapy may be of interest. Acting on more than one cytokine may increase the percentage of responding RA patients as well as the degree of individual patient response.
Cell Mol Biol (Noisy-le-grand) 2001 Jun
PMID:Cytokines in rheumatoid arthritis: is it all TNF-alpha? 1150 74

Bacterial pneumonia remains an important cause of morbidity and mortality worldwide, especially in immune-compromised patients. Cytokines and chemokines are critical molecules expressed in response to invading pathogens and are necessary for normal lung bacterial host defenses. Here we show that interleukin (IL)-17, a novel cytokine produced largely by CD4+ T cells, is produced in a compartmentalized fashion in the lung after challenge with Klebsiella pneumoniae. Moreover, overexpression of IL-17 in the pulmonary compartment using a recombinant adenovirus encoding murine IL-17 (AdIL-17) resulted in the local induction of tumor necrosis factor-alpha, IL-1beta, macrophage inflammatory protein-2, and granulocyte colony-stimulating factor (G-CSF); augmented polymorphonuclear leukocyte recruitment; and enhanced bacterial clearance and survival after challenge with K. pneumoniae. However, simultaneous treatment with AdIL-17 provided no survival benefit after intranasal K. pneumoniae challenge. These data show that IL-17 may have a role in priming for enhanced chemokine and G-CSF production in the context of lung infection and that optimally timed gene therapy with IL-17 may augment host defense against bacterial pneumonia.
Am J Respir Cell Mol Biol 2001 Sep
PMID:Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. 1158 11

Interleukin (IL)-17 is a recently discovered cytokine, which is proposed to play a role in neutrophilic airway inflammation via the release of proinflammatory cytokines and chemokines. To evaluate the role of IL-17 in inflammatory protein production from the airway epithelium, we have analyzed the effects of IL-17 on primary human bronchial epithelial cells (HBECs). Using gene arrays, changes in gene expression in response to IL-17 stimulation were investigated and only IL-8, growth-related oncogene (Gro)alpha, and granulocyte colony-stimulating factor (G-CSF) were found to be upregulated. Secretion of IL-8, Groalpha, and G-CSF in response to IL-17 was measured in HBEC cell culture supernatants by enzyme-linked immunosorbent assay. Upregulation of Groalpha, IL-8, and G-CSF was observed to be 8-, 5-, and 8-fold, respectively, after 48 h stimulation with IL-17. When tested at equivalent concentrations, IL-17 was found to be 2- to 3-fold more potent than tumor necrosis factor (TNF)-alpha in stimulating release of Groalpha and G-CSF from HBECs. In addition, IL-17 was found to synergistically enhance TNF-alpha-induced production of IL-8, Groalpha, and G-CSF. It is proposed that IL-17 may play an important role in neutrophil recruitment via stimulating the release of IL-8, Groalpha, and G-CSF from airway epithelial cells.
Am J Respir Cell Mol Biol 2002 Jun
PMID:Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-alpha, and granulocyte-colony-stimulating factor by human airway epithelial cells. 1203 75

There is increasing evidence that interleukin (IL)-4 can aid in Th1-type inflammatory responses in chronic colitis models. In this study, we evaluated the effects of IL-4 and/or IL-17 on IL-6 secretion in human colonic myofibroblasts. IL-6 secretion was determined by ELISA and Northern blotting. IL-6 secretion was rapidly induced by either IL-4 or IL-17. IL-17 induced IL-6 mRNA expression within 1 h after stimulation, and reached a maximum at 3 h. IL-6 mRNA induction by IL-4 occurred more rapidly. A maximum induction of IL-6 mRNA by IL-4 was observed at 1 h after stimulation, and this was rapidly decreased. The combination of IL-4 plus IL-17 greatly enhanced IL-6 secretion and mRNA expression. In conclusion, IL-4, in particular IL-4 plus IL-17, induced IL-6 secretion in human colonic myofibroblasts. Th2 immune responses might play an important role in the pathogenesis of gut inflammation.
Int J Mol Med 2002 Nov
PMID:Interleukin (IL)-4 and IL-17 synergistically stimulate IL-6 secretion in human colonic myofibroblasts. 1237 6

Interleukin (IL)-17 is produced by activated memory CD4(+) cells and induces cytokines and chemokines that stimulate neutrophil generation and recruitment. Here, we investigated the involvement of IL-17 in the bronchial influx of neutrophils in experimental allergic asthma. Inhalation of nebulized ovalbumin (OVA) by sensitized mice with bronchial eosinophilic inflammation resulting from chronic OVA exposure induced early IL-17 mRNA expression in inflamed lung tissue, concomitant with a prominent bronchial neutrophilic influx. Anti-IL-17 monoclonal antibodies (mAb) injected before allergen inhalation strongly reduced bronchial neutrophilic influx, in a manner equally as potent as the anti-inflammatory dexamethasone. Remarkably, anti-IL-17 mAb significantly enhanced IL-5 levels in both BAL fluid and serum, and aggravated allergen-induced bronchial eosinophilia. In another series of experiments, anti-IL-17 mAb were given repeatedly during the inhalatory challenge phase with OVA of sensitized mice. This treatment regimen abated bronchial neutrophilia in parallel with reduction of bone marrow and blood neutrophilia. In addition, anti-IL-17 mAb treatment elevated eosinophil counts in the bone marrow and bronchial IL-5 production, without alteration of allergen-induced bronchial hyperresponsiveness. In summary, our results demonstrate that IL-17 expression in airways is upregulated upon allergen inhalation, and constitutes the link between allergen-induced T cell activation and neutrophilic influx. Because neutrophils may be important in airway remodeling in chronic severe asthma, targeting IL-17 may hold therapeutic potential in human asthma.
Am J Respir Cell Mol Biol 2003 Jan
PMID:Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. 1249 27

The effect of interleukin (IL)-17 on the activation of inducible nitric oxide (NO) synthase (iNOS) and subsequent production of NO was investigated. IL-17 induced NO production in both mouse and rat endothelial cells in a dose- and time-dependent manner. This was paralleled by the induction of mRNA for iNOS, which was markedly down-regulated by specific antagonists of protein tyrosine kinase, p38 MAP kinase or iNOS transcription factor NF-kappaB. The expression of iNOS transcription factor IRF-1 was also induced by IL-17 and blocked by all three inhibitors, suggesting that the induction of iNOS by IL-17 might be partly exerted through IRF-1 activation. Neutralization with the specific antibody showed that endogenous IL-17 is involved in T cell-mediated NO production in endothelial cells and NO-dependent suppression of T cell growth. These data indicate that IL-17-triggered iNOS activation in endothelial cells might participate in regulation of the T cell-dependent inflammatory response.
Cell Mol Life Sci 2003 Mar
PMID:The role of interleukin-17 in inducible nitric oxide synthase-mediated nitric oxide production in endothelial cells. 1273 11

Lung epithelial cells contribute to local inflammation by the production of pro-inflammatory mediators like interleukin (IL)-8 and IL-6. Although their production depends on gene transcription, previous studies showed that post-transcriptional mechanisms modulate IL-8 and IL-6 production. Human lung epithelial cells turn from normoresponsive into hyperresponsive IL-8- and IL-6-producing cells when their IL-8 and IL-6 mRNA degradation is reduced. We hypothesized that IL-17, a mediator predominantly released by memory T cells and present in airways of individuals with asthma, would modulate rather than induce IL-8 and IL-6 production by both human lung epithelial cells and fibroblasts. We show here for both cell types that IL-17 was a weak stimulus of IL-8 and IL-6 production, but markedly enhanced IL-8 and IL-6 responses to another stimulus, such as tumor necrosis factor-alpha. This modulatory effect of IL-17 was paralleled by a reduced IL-8 and IL-6 mRNA degradation, with no effect on IL-8 and IL-6 gene transcription. In conclusion, IL-17 particularly affects post-transcriptional regulation of IL-8 and IL-6 expression leading to enhanced IL-8 and IL-6 responses to secondary stimuli, and is only a weak proinflammatory stimulus by itself. This poses the interesting concept that by releasing IL-17 from memory T cells, the adaptive immune system instructs lung structural cells as part of the innate immune system to respond more vigorously.
Am J Respir Cell Mol Biol 2005 Jul
PMID:Interleukin-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells. 1584 64

IL-17 is a major proinflammatory cytokine secreted by activated T-lymphocytes that accumulates in the inflamed joints of rheumatoid arthritis (RA) patients. Additional IL-17-related molecules and their receptors have been discovered and may also contribute to RA pathogenesis. We examined the expression of the prototypic IL-17 (IL-17A) and its homologs, IL-17B-F, by RT-PCR analyses of synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from RA patients. We also tested for induction of the IL-17 receptor homologs upon stimulation of the fibroblast-like synoviocytes (FLSs) of RA patients with IL-17. The patients' SFMCs expressed IL-17C, E and F in addition to IL-17A. As in the case of IL-17, IL-15 appears to be the major inducer of these homologs in RA SFMCs. We detected transcripts of IL-17R, as well as those of IL-17RB, C and D, in the FLSs of RA patients. Whereas IL-17R expression increased upon in vitro stimulation with IL-17, expression of IL-17RB, C and D was unchanged. However the possibility of cross-interaction between other IL-17 homologs and receptor isoforms remains to be investigated. Our data suggest that these additional homologs should also be considered as targets for immune modulation in the treatment of RA joint inflammation.
Mol Cells 2005 Apr 30
PMID:Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. 1587 99

Recent data indicate that the proinflammatory cytokine, interleukin (IL)-17, stimulates certain effector functions of human macrophages. We evaluated whether IL-17 mediates allergen-induced accumulation of airway macrophages and, if so, whether such an effect relates to the control of macrophage recruitment and survival. BALB/c mice were sensitized and challenged with ovalbumin. Three hours before challenge an anti-mouse IL-17 mAb (a-IL-17) was administered. Sampling was conducted 24 h after the allergen challenge. In vitro chemotaxis assay for blood monocytes and culture of airway macrophages, immunocytochemistry for Fas-antigen, and matrix metalloproteinase-9 (MMP-9) were used to determine the effect of IL-17 on the recruitment, survival, and activity of airway macrophages. A-IL-17 reduced the number of airway neutrophils and macrophages after allergen challenge. In vitro, recombinant IL-17 induced migration of blood monocytes and prolonged survival of airway macrophages. A-IL-17 also increased the expression of Fas-antigen in airway macrophages in vivo. Finally, the expression of MMP-9 by airway neutrophils and macrophages in vivo was downregulated by a-IL-17. This study indicates that endogenous IL-17 mediates the accumulation of macrophages during allergen-induced airway inflammation. IL-17 exerts its effects by acting directly on airway macrophages by promoting their recruitment and survival. Furthermore, IL-17 is involved in controlling the proteolytic activity of macrophages and neutrophils in allergen-induced airway inflammation.
Am J Respir Cell Mol Biol 2005 Sep
PMID:Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation. 1590 16


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