Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that fibroblasts play a crucial role in pathophysiological extracellular matrix remodelling. The aim of this project is to elucidate their role in normal physiological remodelling. Specifically, the remodelling of the human cervix during pregnancy, resulting in an enabled passage of the child, is used as the model system. Fibroblast cultures were established from cervices of non-pregnant women, women after 36 weeks of pregnancy and women directly after partus. The cells were immunostained and quantified by western blots for differentiation markers. The cultures were screened for cytokine and metalloproteinase production and characterized by global proteome analysis. The cell cultures established from partal donors differ significantly from those from non-pregnant donors, which is in accordance with in vivo findings. A decrease in alpha-smooth actin and prolyl-4-hydroxylase and an increase in interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMP)-1 and MMP-3 were observed in cultures from partal donors. 2D-gel electrophoresis followed by mass spectrometry showed that the expression of 59 proteins was changed significantly in cultures of partal donors. The regulated proteins are involved in protein kinase C signalling, Ca2+ binding, cytoskeletal organization, angiogenesis and degradation. Our data suggest that remodelling of the human cervix is orchestrated by fibroblasts, which are activated or recruited by the inflammatory processes occurring during the ripening cascade.
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PMID:The importance of fibroblasts in remodelling of the human uterine cervix during pregnancy and parturition. 1733 76

Periodontitis is characterized by periodontal tissue destruction. Since interleukin-17 (IL-17) has been reported to up-regulate IL-1beta and tumor necrosis factor-alpha (TNF-alpha), it was hypothesized that it is increased in periodontitis and up-regulates these cytokines and tissue-destructive matrix metalloproteinases (MMP) in local migrant and resident cells. Immunocytochemistry disclosed elevated IL-1beta, TNF-alpha, and IL-17 levels in periodontitis. These cytokines induced proMMP-1 and especially MMP-3 in gingival fibroblasts, whereas MMP-8 and MMP-9 were not induced. IL-17 was less potent as a direct MMP inducer than IL-1beta and TNF-alpha, but it induced IL-1beta and TNF-alpha production from macrophages, and IL-6 and IL-8 from gingival fibroblasts. In accordance with these findings, immunocytochemistry disclosed that MMP-1 and MMP-3 were increased in periodontitis. Gingival fibroblasts may play an important role in tissue destruction in periodontitis via cytokine-inducible MMP-1 and MMP-3 production, in which IL-17 plays a role as a key regulatory cytokine.
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PMID:MMPs, IL-1, and TNF are regulated by IL-17 in periodontitis. 1738 30

Interleukin (IL)-31 is mainly produced by CD4+ T cells, in particular T cells skewed toward a Th2 phenotype. Here we report for the first time that IL-31 stimulates secretion of proinflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) from human colonic subepithelial myofibroblasts (SEMFs). The effects of IL-31 were investigated by cDNA microarrays, enzyme-linked immunosorbent assay, and real-time PCR. IL-31 effectively induced chemokines [IL-8, GRO-alpha (growth-related oncogene-alpha), MCP-3 (monocyte chemoattractant protein-3), CXCL3, CCL13 and CCL15], proinflammatory cytokines (IL-6, IL-16 and IL-32) and matrix metalloproteinases (MMP-1, MMP-3, MMP-25 and MMP-7). IL-31 dose-dependently induced secretion of IL-6, IL-8, GRO-alpha, MCP-3, MMP-1 and MMP-3. The effects of IL-31 were comparable to the effects of IL-17A. IL-31 and IL-17A showed additive effects on IL-6, IL-8, GRO-alpha, MCP-3, MMP-1 and MMP-3 secretion. In conclusion, we demonstrated that IL-31 is a potent inducer of proinflammatory mediators in human colonic SEMFs. IL-31 may function as a proinflammatory cytokine derived from Th2 cells.
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PMID:Interleukin-31 stimulates production of inflammatory mediators from human colonic subepithelial myofibroblasts. 1748 27

Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 is a MAPKKK in the MAPK (i.e. ERK) pathway, and the Tpl2-MEK-ERK signaling pathway is activated by the pro-inflammatory mediators TNFalpha, interleukin (IL)-1beta, and bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, Tpl2 is required for TNFalpha expression. Thus, pharmacologic inhibition of Tpl2 should be a valid approach to therapeutic intervention in the pathogenesis of rheumatoid arthritis and other inflammatory diseases in humans. We have developed a series of highly selective and potent Tpl2 inhibitors, and in the present study we have used these inhibitors to demonstrate that the catalytic activity of Tpl2 is required for the LPS-induced activation of MEK and ERK in primary human monocytes. These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood. In rheumatoid arthritis fibroblast-like synoviocytes these inhibitors block ERK activation, cyclooxygenase-2 expression, and the production of IL-6, IL-8, and prostaglandin E(2), and the matrix metalloproteinases MMP-1 and MMP-3. Taken together, our results show that inhibition of Tpl2 in primary human cell types can decrease the production of TNFalpha and other pro-inflammatory mediators during inflammatory events, and they further support the notion that Tpl2 is an appropriate therapeutic target for rheumatoid arthritis and other human inflammatory diseases.
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PMID:Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. 1784 81

The purpose of this study was to investigate the possible involvement of synovium in cartilage destruction in osteoarthritis (OA) patients. Using human primary synovial fibroblasts (HPSFs), we examined the effects of glucosamine (GLN) on the regulation of the expression of matrix metalloproteinases (MMP-1, -2, and -13) and chemokines (IL-8, MCP-1, and RANTES) as well as the involvement of MAPK signal pathways (JNK, ERK, and p-38) and the transcription factor of NF-kappaB on the present or absence of interleukin (IL)-1beta. Our experiments showed that protein production and mRNA expressions of MMP-1, MMP-3, MMP-13, IL-8, MCP-1, and RANTES were downregulated by treatment with glucosamine in HPSFs. The results further showed that GLN could inhibit IkappaBalpha phosphorylation and IkappaBalpha degradation leading to inhibition of the translocation of NF-kappaB to nuclei. However, GLN upregulated MAPKs pathways in HPSFs cells with or without IL-1beta. The results suggest that the inhibition of MMP-1, -3, and -13 expressions as well as IL-8, MCP-1, and RANTES productions by GLN might mediate suppression of NF-kappaB signal pathways, and HPSFs seem to have a potential functions as an alternative source of MMPs and chemokines for inducing the degradation of cartilage in OA.
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PMID:Disease-modifying effects of glucosamine HCl involving regulation of metalloproteinases and chemokines activated by interleukin-1beta in human primary synovial fibroblasts. 1808 Mar 21

Human recombinant IL-1beta and TNFalpha have been previously used to induce a cytokine response in canine chondrocytes. In order to establish this functional relation in a homologous system in vitro, we have developed both 2D and 3D models of inflammatory arthritis using canine recombinant cytokines in canine articular chondrocytes. IL-1beta and TNFalpha were cloned and subsequently expressed in Escherichia coli. The purified recombinant canine cytokines were used to simulate inflammation in vitro and the expression of typical inflammation markers such as proinflammatory cytokines (IL-1beta, IL-6, IL-8, GM-CSF and TNFalpha), enzyme mediators (MMP-3 MMP-13, iNOS, COX-2) and their catabolites (NO, PGE(2)) was measured. High expression of proinflammatory cytokines, enzyme mediators and their catabolites was only observed in IL-1beta/TNFalpha stimulated cells. We conclude that the canine IL-1beta and TNFalpha generated in this study are biologically active and equally effective in the canine cell culture systems. Inducing an inflammatory pathway by canine exogenous cytokines in canine chondrocytes provides a useful tool for the study of canine inflammatory arthritis.
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PMID:Quantification of cytokines and inflammatory mediators in a three-dimensional model of inflammatory arthritis. 1834 81

In this study, we compared the gene expression profiles of non-syndromic hyperplastic dental follicle (HDF) fibroblasts and normal dental follicle (NDF) fibroblasts using cDNA microarrays, quantitative PCR, and immunohistochemical staining. Microarray analysis showed that several collagens genes were upregulated in the HDFos, including collagen types I, IV, VIII, and XI and TIMP-1, -3, and -4 (fold ratio > 2.0). In contrast, the expression of MMP-1, -3, -10, and -16 together with IL-8 was more than two fold downregulated. The differential expression of the genes encoding alkaline phosphatase, MMP-1, -3, -8, and IL-8 was confirmed by quantitative RT-PCR, while that of 24 HDFs and 18 NDFs was confirmed by immunohistochemical analysis. However, HDFs showed stronger expression of MMP-3 than NDFs (P < 0.001). Collectively, these results indicate that defective regulation of MMPs mediating connective tissue remodeling may be responsible for abnormal tooth eruption.
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PMID:Downregulation of matrix metalloproteinases in hyperplastic dental follicles results in abnormal tooth eruption. 1845 54

The aims of the present study were to compare the levels of mRNA and protein expression of matrix metalloproteinase (MMP)-1, -3, -8 and -9 in human cervical tissue in preterm and term labor as well as not in labor and to determine if corticotropin-releasing hormone (CRH) has an effect on MMP-1, -3 and interleukin (IL)-8 secretion in both preterm and term cervical fibroblasts. Cervical biopsies were taken from 60 women: 18 at preterm labor, 7 at preterm not in labor, 18 at term labor and 17 at term not in labor. ELISA and Immulite were used for protein and real-time RT-PCR for mRNA analysis. Cervical fibroblast cultures were incubated for 18 h with different CRH concentrations (10(-13)-10(-6) M). The mRNA expression of MMP-1, -3 and -9 was higher in laboring groups compared with term not in labor. Protein levels of MMP-8 and -9 were higher in term in labor group compared with non-laboring groups. There were no significant differences in mRNA and protein expression between the preterm and respective term control groups. CRH significantly increased secretion of IL-8 in preterm and term cervical fibroblasts compared with controls. The secretion of IL-8 and MMP-1 was significantly higher and MMP-3 secretion lower in preterm cervical fibroblasts. In conclusion, cervical ripening at preterm seems to be a similar inflammatory process as at term with CRH involved. However, preterm and term cervical fibroblasts might have different phenotypes based on different secretion patterns of IL-8, MMP-1 and MMP-3.
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PMID:Different secretion patterns of matrix metalloproteinases and IL-8 and effect of corticotropin-releasing hormone in preterm and term cervical fibroblasts. 1892 47

Previous studies show that the chemokine CXCL16 and its receptor CXCR6 are likely to contribute to prostate cancer (PCa). In this investigation, the role of the CXCR6 receptor in PCa was further explored. CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 showed strong epithelial staining that correlated with Gleason score. In vitro and in vivo studies in PCa cell lines suggested that alterations in CXCR6 expression were associated with invasive activities and tumor growth. In addition, CXCR6 expression was able to regulate expression of the proangiogenic factors interleukin (IL)-8 or vascular endothelial growth factor (VEGF), which are likely to participate in the regulation of tumor angiogenesis. Finally, we found that CXCL16 signaling induced the activation of Akt, p70S6K, and eukaryotic initiation factor 4E binding protein 1 included in mammalian target of rapamycin (mTOR) pathways, which are located downstream of Akt. Furthermore, rapamycin not only drastically inhibited CXCL16-induced PCa cell invasion and growth but reduced secretion of IL-8 or VEGF levels and inhibited expression of other CXCR6 targets including CD44 and matrix metalloproteinase 3 in PCa cells. Together, our data shows for the first time that the CXCR6/AKT/mTOR pathway plays a central role in the development of PCa. Blocking the CXCR6/AKT/mTOR signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for PCa.
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PMID:CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway. 1907 6

The aim of this study was to assess sputum levels of the metalloproteinases MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2, as well as MMPs/TIMPs ratios in relation to exhaled NO (eNO) and sputum NOs (nitrates and nitrites) and IL8 obtained from chronic obstructive pulmonery disease (COPD) patients, healthy non-smokers, and healthy smokers. We found higher levels of TIMP-1 (118.9 ng/ml) and TIMP-2 (3.75 ng/ml) in COPD patients than in healthy smokers (17.7 ng/ml, P<0.03; 0.51 ng/ml, P>0.05, respectively) and healthy non-smokers (84.6 ng/ml, P>0.05; 1.61 ng/ml, P>0.05, respectively). We also observed significant positive correlations between concentrations of NOs and MMP-1, MMP-2, MMP-3, and TIMP-2 (r=0.37, P<0.02; r=0.60, P<0.0001; r=0.56, P<0.0004 and r=0.47 P<0.004, respectively) in COPD patients. IL8, MMP-2, MMP-3, and TIMP-2 levels in induced sputum were negatively correlated with airway obstruction, i.e., FEV(1)/FVC (r=-0.61, P<0.00009; r=-0.41, P<0.01; r=-0.38, P<0.02; r=-0.49, P<0.002). Our study points to a potentially pathogenic role of stromelysin-1 (MMP-3) in COPD.
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PMID:Induced sputum metalloproteinases and their inhibitors in relation to exhaled nitrogen oxide and sputum nitric oxides and other inflammatory cytokines in patients with chronic obstructive pulmonary disease. 1921 8


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