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)

Even today prematurity is the major cause of perinatal mortality. Prematurity has multiple causes. There is a growing body of evidence supporting the association between silent intrauterine infection and preterm birth. Bacterial products may activate macrophages ubiquitous present in the decidua, placenta and fetal membranes. These cells after activation secrete a large variety of mediators including tumour necrosis factor alpha (TNFalpha) and interleukin (IL)-1. Besides these cytokines IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, epidermal growth factor, granulocyte-colony stimulating factor and transforming growth factor beta have been identified in intrauterine tissues and in the amniotic fluid. The majority of these substances (TNFalpha, IL-1, IL-2, IL-3, IL-6) can stimulate the prostaglandin-biosynthesis by intrauterine tissues (amnion, chorion, decidua), some of them have antiinflammatory effects (IL-10, transforming growth factor alpha). These effects are mediated by receptors on the target cells; specific receptor antagonists (for example for IL-1) were found in high concentrations in amniotic fluid during normal pregnancy. This cytokine network is in a sensitive balance and probably associated with an uncomplicated course of pregnancy. Systemic or localized infections as well as tissue injury initiate the induction of the prostaglandin synthesis cascade thus leading to pregnancy loss via augmented cytokine secretion. Furthermore, cytokines may be involved in the regulation of preterm and term cervical ripening. The changes in mechanical properties of the cervix are associated with a reduction of collagen content and alterations in the glycosaminoglycan pattern within the cervical extracellular matrix. IL-1 can stimulate the synthesis of collagenases, and IL-8 may play an important role in the regulation of the invasion of neutrophilic granulocytes into the cervical stroma with subsequent degranulation and release of proteases. The cytokine-stimulated collagenase production in the fetal membranes is responsible for the reduction of their tensile strength and may be associated with rupture of the membranes. The cytokine network seems to be a sensitive regulation system. Disturbances of its balance by environmental (e.g. infection) or intrauterine influences (e. g. extension by the fetus) may lead to termination of pregnancy.
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PMID:[The role of cytokines in the induction of labor, cervical ripening and rupture of the fetal membranes]. 1676 18

Baicalin is a flavonoid compound purified from the medicinal plant Scutellaria baicalensis Georgi and has been reported to possess anti-inflammatory activity through its ability to complex with chemokines and thus reduces the capacity of chemokines to bind and activate their receptors. In the present study, we investigated whether baicalin could block polymorphonuclear leukocytes (PMNs) degranulation induced by interleukin (IL)-8, a CXC chemokine. Human PMNs were isolated from the peripheral blood of periodontal healthy donors and incubated with various concentrations of IL-8 (preincubated with or without baicalin). The morphology of PMNs was examined by transmission electron microscopy and extracellular concentration of granule component matrix metalloproteinase-8 (MMP-8) was detected by enzyme-linked immunosorbent assay (ELISA). Results showed that IL-8 could significantly induce MMP-8 release from PMNs when compared to control, and its inductive activity was concentration-dependent. But when preincubated with various concentrations of baicalin, the amount of MMP-8 release from PMNs decreased significantly. The present study concludes that baicalin could block MMP-8 release from PMNs induced by IL-8, which suggests that it may play an important role in the prevention and treatment of periodontal disease.
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PMID:Inhibitory effect of flavonoid baicalin on degranulation of human polymorphonuclear leukocytes induced by interleukin-8: potential role in periodontal diseases. 1696 73

The widespread distribution of Toll-like receptors (TLRs) and their ligands raises the question whether they contribute to the production of inflammatory and tissue destructive molecules in rheumatoid arthritis (RA). We examined the expression and function of TLR2 and TLR4 and their downstream signaling adaptors MyD88 and Mal/TIRAP in synovial membrane cultures from RA tissue. Both TLR2 and TLR4 were detected by flow cytometry, and stimulation with TLR2 and TLR4 ligands augmented the spontaneous production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, indicating that TLR2 and TLR4 are functional in these cultures. In addition, overexpression of dominant-negative forms of MyD88 and Mal/TIRAP significantly down-regulated the spontaneous production of cytokines tumor necrosis factor-alpha, IL-6, and vascular endothelial growth factor, and enzymes MMP-1, MMP-2, MMP-3, and MMP-13 in RA synovial membrane cell cultures. Because TLR2 and TLR4 require both MyD88 and Mal/TIRAP for signaling, this study suggests that TLR function may regulate the expression of these factors in the RA synovium. Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells. Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA.
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PMID:The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. 1725 20

The molecular basis and downstream targets of oral selenium supplementation in individuals with elevated risk of cancer due to chronic exposure from environmental carcinogens has been largely unexplored. In this study, we investigated genome-wide differential gene expression in peripheral blood mononuclear cells (PBMC) from individuals with pre-malignant arsenic (As)-induced skin lesions before and after 6 months daily oral supplementation of 200 microg L-selenomethionine. The Affymetrix GeneChip Human 133A 2.0 array, containing probes for 22,277 gene transcripts, was used to assess gene expression. Three different normalization methods, RMA (robust multi-chip analysis), GC-RMA and PLIER (Probe logarithmic intensity error), were applied to explore differentially expressed genes. We identified a list of 28 biologically meaningful, significantly differentially expressed genes. Genes up-regulated by selenium supplementation included TNF, IL1B, IL8, SOD2, CXCL2 and several other immunological and oxidative stress-related genes. When mapped to a biological association network, many of the differentially expressed genes were found to regulate functional classes such as fibroblast growth factor, collagenase, matrix metalloproteinase and stromelysin-1, and thus, considered to affect cellular processes like apoptosis, proliferation and others. Many of the significantly up-regulated genes following selenium-supplementation were previously found by us to be down-regulated in a different set of individuals with As-induced skin lesions compared to those without. In conclusion, findings from this study may elucidate the biological effect of selenium supplementation in humans. Additionally, this study suggests that long-term selenium supplementation may revert some of the gene expression changes presumably induced by chronic As exposure in individuals with pre-malignant skin lesions.
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PMID:Changes in gene expression profiles in response to selenium supplementation among individuals with arsenic-induced pre-malignant skin lesions. 1729 63

The aim of this study was to investigate if coherence length is of importance in laser phototherapy. Twenty patients with moderate periodontitis were selected. After oral hygiene instructions, scaling and root planing (SRP), one side of the upper jaw was randomly selected for HeNe (632.8 nm, 3 mW) or InGaAlP (650 nm, 3 mW) laser irradiation. One week after SRP, the following parameters were measured: pocket depth, gingival index, plaque index, gingival crevicular fluid volume, matrix metalloproteinase (MMP-8), interleukin (IL-8) and subgingival microflora. The irradiation (180 s per point, energy 0.54 J) was then performed once a week for 6 weeks. At the follow up examination, all clinical parameters had improved significantly in both groups. A more pronounced decrease of clinical inflammation was observed after HeNe treatment. MMP-8 levels were considerably reduced on the HeNe side, while there was no difference for IL-8 or microflora. Coherence length appears to be an important factor in laser phototherapy.
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PMID:The importance of coherence length in laser phototherapy of gingival inflammation: a pilot study. 1733 77

We identify matrix metalloproteinase (MMP)-8, the polymorphonuclear (PMN) leukocyte collagenase, as a critical mediator initiating lipopolysaccharide (LPS)-responsiveness in vivo. PMN infiltration towards LPS is abrogated in Mmp8-null mice. MMP-8 cleaves LPS-induced CXC chemokine (LIX) at Ser(4)-Val(5) and Lys(79)-Arg(80). LIX bioactivity is increased upon N-terminal cleavage, enhancing intracellular calcium mobilization and chemotaxis upon binding its cognate receptor, CXCR2. As there is no difference in PMN chemotaxis in Mmp8-null mice compared with wild-type mice towards synthetic analogues of MMP-8-cleaved LIX, MMP-8 is not essential for extravasation or cell migration in collagenous matrices in vivo. However, with biochemical redundancy between MMPs 1, 2, 9, and 13, which also cleave LIX at position 4 approximately 5, it was surprising to observe such a markedly reduced PMN infiltration towards LPS and LIX in Mmp8-/- mice. This lack of physiological redundancy in vivo identifies MMP-8 as a key mediator in the regulation of innate immunity. Comparable results were found with CXCL8/IL-8 and CXCL5/ENA-78, the human orthologues of LIX. MMP-8 cleaves CXCL8 at Arg(5)-Ser(6) and at Val(7)-Leu(8) in CXCL5 to activate respective chemokines. Hence, rather than collagen, these PMN chemoattractants are important MMP-8 substrates in vivo; PMN-derived MMP-8 cleaves and activates LIX to execute an in cis PMN-controlled feed-forward mechanism to orchestrate the initial inflammatory response and promote LPS responsiveness in tissue.
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PMID:LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. 1737 98

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

Compressive stress may be involved in temporomandibular joint (TMJ) synovitis, but its mechanism has not been fully elucidated. We hypothesized that mechanical stress to the synovial cells of the TMJ potentially causes degenerative changes in temporomandibular joint disease. We examined the effect of cyclic compressive loading on three-dimensionally engineered constructs using human TMJ synovium-derived cells in vitro. Human TMJ synovium-derived cells were cultured onto collagen scaffolds, resulting in three-dimensional constructs. Cyclic compression loading was applied to the constructs by means of a custom-designed apparatus. DNA amount, apoptotic cells, and mRNA levels for inflammatory cytokines were analyzed. The protein expression and activity of MMPs were examined. DNA amount or apoptotic cell number was unchanged by loading. MMP-2, -3, and IL-8 mRNA expression was up-regulated by the compression, and both MMP-1 and -3 protein expression and MMP-2 activity were detected. Thus, compression of human TMJ synovium-derived cells appears to modulate inflammatory cytokines.
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PMID:Effects of compressive loading on human synovium-derived cells. 1765 11

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


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