scholarly journals Slit2 Regulates Hyaluronan & Cytokine Synthesis in Fibrocytes: Potential Relevance to Thyroid-Associated Ophthalmopathy

2020 ◽  
Vol 106 (1) ◽  
pp. e20-e33
Author(s):  
Roshini Fernando ◽  
Terry J Smith
Keyword(s):  
Gene Expression ◽  
Glucose Dehydrogenase ◽  
Expression Patterns ◽  
Healthy Donors ◽  
Tnf Α ◽  
Thyroid Associated Ophthalmopathy ◽  
Ha Synthase ◽  
Factor Α ◽  
Orbital Fibroblasts ◽  
Necrosis Factor

Abstract Context CD34+ fibrocytes have been implicated in development of thyroid-associated ophthalmopathy (TAO), a consequential autoimmune manifestation of Graves disease (GD). In TAO, CD34+ fibrocytes appear to masquerade as CD34+ orbital fibroblasts mixed with CD34- OF (collectively, GD-OF). Slit2, an axon guidance glycoprotein, is expressed by CD34- OF and attenuates GD-OF gene expression. Cardinal features of TAO include hyaluronan (HA) accumulation and cytokine-driven inflammation. Objective Compare expression of HA synthase isoenzymes (HAS1-3), UDP-glucose dehydrogenase (UGDH), synthesis of HA, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in fibrocytes and GD-OF. Determine whether Slit2 alters gene expression patterns. Design/Setting/Participants Patients with TAO and healthy donors were recruited from an academic practice. Main Outcome Measures Real-time polymerase chain reaction, HA, IL-6, and TNF-α immunoassays. Results HA synthesis and release from fibrocytes is substantially lower than in GD-OF. HAS1 expression dominates in fibrocytes while HAS2 in GD-OF. In contrast, HAS2 and UGDH expression dominate GD-OF and localize to CD34- OF. Recombinant human Slit2 (rhSlit2) substantially upregulates HA synthesis and HAS2 expression in fibrocytes but attenuates IL-6 and TNF-α production in these cells. In contrast, knocking down Slit2 in GD-OF reduces HA synthesis and HAS2 and UGDH expression while upregulating IL-6 and TNF-α. Conclusion The dramatic differences in HA, IL-6, and TNF-α production, and HAS and UGDH expression found in fibrocytes and GD-OF appear, at least in part, to be attributable to Slit2. These findings provide novel insight into the differences in gene expression exhibited by CD34+ fibrocytes and CD34+ OF and therefore reveal important aspects of disease pathogenesis.

scholarly journals Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains

Gut ◽  
1997 ◽  
Vol 41 (4) ◽  
pp. 442-451 ◽  
Author(s):  
Y Yamaoka ◽  
M Kita ◽  
T Kodama ◽  
N Sawai ◽  
K Kashima ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Expression Patterns ◽  
Mucosal Inflammation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Biopsy Specimens ◽  
Tnf Α ◽  
Polymerase Chain ◽  
H Pylori ◽  
Factor Α ◽  
Necrosis Factor

Background—Helicobacter pyloristrains possessing the cagA gene are thought to induce interleukin 8 (IL-8) in gastric mucosa. However, it is still unclear whether a relation exists between the cagA gene and the expression patterns of cytokines other than IL-8.Aims—To investigate the relation between the cagA gene and the production of various cytokine proteins using an enzyme linked immunosorbent assay (ELISA).Patients and methods—In 184 patients, the cagA gene was detected by polymerase chain reaction (PCR), and levels of production of IL-1β, IL-6, IL-7, IL-8, IL-10, and tumour necrosis factor α (TNF-α) in antral biopsy specimens were measured by ELISA.Results—Mucosal levels of IL-1β, IL-6, IL-8, and TNF-α were significantly higher in H pyloripositive than in H pylori negative patients. Furthermore, the mucosal levels of IL-1β and IL-8 were significantly higher in specimens infected with cagApositive strains than in those infected with cagAnegative strains. In H pylori positive patients, the mucosal level of IL-8 was closely correlated with that of IL-1β (p<0.0001), and the mucosal level of IL-6 was closely correlated with that of TNF-α (p<0.0001).Conclusion—These findings suggest that the ability to induce cytokines differs among the strains;cagA+ strains induce various kinds of cytokines and may cause severe inflammation, whereascagA− strains induce IL-8 and IL-1β only weakly and may cause only mild inflammation. However, as most patients infected with the cagA+ strains have gastritis, these strains may not be equivalent to ulcerogenic strains.

scholarly journals Effects of acanthoic acid on TNF-α gene expression and haptoglobin synthesis

1998 ◽  
Vol 7 (4) ◽  
pp. 257-259 ◽  
Author(s):  
H-S. Kang ◽  
H. K. Song ◽  
J-J. Lee ◽  
K-H. Pyun ◽  
I. Choi
Keyword(s):  
Gene Expression ◽  
Biological Function ◽  
Acute Phase Protein ◽  
Inhibitory Effects ◽  
Rt Pcr ◽  
Tnf Α ◽  
Phase Protein ◽  
Factor Α ◽  
Necrosis Factor ◽  
Acanthoic Acid

Tumour necrosis factor-α (TNF-α) is a major proinflammatory cytokine inducing the synthesis and release of many inflammatory mediators. It is involved in immune regulation, autoim mune diseases, and inflammation. Our previous study demonstrated that acanthoic acid, (-)-pimara-9(11), 15-dien19-oic acid, a pimaradiene diterpene isolated fromAcanth opanax koreanum, inhibited TNF-α production. To extend our understanding of inhibitory effects of acanthoic acid on TNF-α production, its effects on TNF-α gene expression was tested. Based on the results from RT-PCR and promoter analysis of TNF-α, it was found that acanthoic acid suppressed TNF-α gene expression. But the same concentration of acanthoic acid had no effect on IL-6 gene expression. Haptoglobin is an acute phase protein which is induced by TNF-α. When liver cells were treated with acanthoic acid, haptoglobin synthesis was blocked by acanthoic acid. These data confirmed that acanthoic acid inhibited gene expression and biological function of TNF-α.

Peroxynitrite production by TNF-α and IL-1β: implication for suppression of osteoblastic differentiation

2000 ◽  
Vol 278 (6) ◽  
pp. E1031-E1037 ◽  
Author(s):  
Hisako Hikiji ◽  
Wee Soo Shin ◽  
Toshiyuki Koizumi ◽  
Tsuyoshi Takato ◽  
Takafumi Susami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis ◽  
Osteoblastic Differentiation ◽  
No Donor ◽  
Osteoblastic Activity ◽  
Tnf Α ◽  
Osteocalcin Gene ◽  
Per Se ◽  
Factor Α ◽  
Necrosis Factor

To determine the roles of nitric oxide (NO) and its metabolite, peroxynitrite (ONOO−), on osteoblastic activation, we investigated the effects of a NO donor [ethanamine, 2,2′-(hydroxynitrosohydrazono)bis- (dNO)], an [Formula: see text] donor (pyrogallol), and an ONOO− scavenger (urate) on alkaline phosphatase (ALPase) activity and osteocalcin gene expression, which are indexes of osteoblastic differentiation. dNO elevated ALPase activity in the osteogenic MC3T3-E1 cell line. The combination of dNO and pyrogallol reduced both ALPase activity and osteocalcin gene expression. Because both indexes were recovered by urate, ONOO−, unlike NO itself, inhibited the osteoblastic differentiation. Furthermore, treatment with a combination of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was found to yield ONOO−as well as NO and [Formula: see text]. The reductions in ALPase activity and osteocalcin gene expression were also restored by urate. We conclude that ONOO− produced by TNF-α and IL-1β, but not NO per se, would overcome the stimulatory effect of NO on osteoblastic activity and inhibit osteoblastic differentiation.

Effect of interleukin-1β and tumor necrosis factor-α on gene expression in human endothelial cells

2003 ◽  
Vol 284 (6) ◽  
pp. C1577-C1583 ◽  
Author(s):  
Baiteng Zhao ◽  
Salomon A. Stavchansky ◽  
Robert A. Bowden ◽  
Phillip D. Bowman
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Umbilical Vein ◽  
Interleukin 1Β ◽  
Tnf Α ◽  
Factor Α ◽  
Microarray Expression ◽  
Necrosis Factor

Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are two major cytokines that rise to relatively high levels during systemic inflammation, and the endothelial cell (EC) response to these cytokines may explain some of the dysfunction that occurs. To better understand the cytokine-induced responses of EC at the gene expression level, human umbilical vein EC were exposed to IL-1β or TNF-α for various times and subjected to cDNA microarray analyses to study alterations in their mRNA expression. Of ∼4,000 genes on the microarray, expression levels of 33 and 58 genes appeared to be affected by treatment with IL-1β and TNF-α, respectively; 25 of these genes responded to both treatments. These results suggest that the effects of IL-1β and TNF-α on EC are redundant and that it may be necessary to suppress both cytokines simultaneously to ameliorate the systemic response.

Tumour necrosis factor-α gene expression and production in human umbilical arterial endothelial cells

2000 ◽  
Vol 98 (4) ◽  
pp. 461-470 ◽  
Author(s):  
Thomas NEUHAUS ◽  
Gudrun TOTZKE ◽  
Elisabeth GRUENEWALD ◽  
Hans-Peter JUESTEN ◽  
Agapios SACHINIDIS ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Dependent Manner ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Necrosis Factor

Endothelial cells act as an interface between the blood and tissues, and are known to be involved in inflammatory processes. These cells are responsive to and produce different cytokines. Tumour necrosis factor-α (TNF-α) not only is one of the most important inflammatory peptides, but also can be induced by lipopolysaccharide (LPS). The focus of the present study was on TNF-α gene expression and production in human umbilical arterial endothelial cells (HUAEC), including the kinetics of this process. Interleukin-1α (IL-1α), LPS and TNF-α, which are all known to be elevated in septic shock, were used as stimulators at concentrations commonly found in patients with sepsis. Through the use of reverse transcriptase/PCR, immunohistochemical reactions and ELISA techniques, we showed that, in HUAEC, all three stimuli were able to induce gene expression and production of TNF-α. Furthermore, this induction by IL-1α, LPS and TNF-α occurred in a time- and concentration-dependent manner in these cells. TNF-α expression and production was induced by all three agents at concentrations commonly found in patients with sepsis. TNF-α mRNA was observed within 30 min regardless of the stimulus used, but the levels peaked at different times. Since it is well established that TNF-α is able to induce the synthesis of IL-1α in endothelial cells and, as shown in the present study, TNF-α and IL-1α are themselves able to induce the synthesis of TNF-α in endothelial cells, an autocrine potentiation of cytokine release in sepsis can be proposed. This situation could lead to a locally acting ‘vicious cycle’ which, when considered in addition to the known ability of TNF-α to induce apoptosis, could mean that various organs will be damaged, a condition associated with sepsis. Thus these results provide further evidence for the important role played by the endothelium in inflammation.

scholarly journals Turnour necrosis factor stimulates endothelin-1 gene expression in cultured bovine endothelial cells

1992 ◽  
Vol 1 (4) ◽  
pp. 263-266 ◽  
Author(s):  
Silvia Orisio ◽  
Marina Morigi ◽  
Carla Zoja ◽  
Norberto Perico ◽  
Giuseppe Remuzzi
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Hypotensive Effect ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Aortic Endothelial Cells ◽  
Endothelin 1 ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

We have studied the effect of human recombinant tumour necrosis factor-α (TNF-α) on gene expression and production of endothelin-1 in cultured bovine aortic endothelial cells. TNF-α (10 and 100 ng ml−1) increased in a time dependent manner the preproendothelin-1 mRNA levels in respect to unstimulated endothelial cells. TNF-α induced endothelin-1 gene expression was associated with a parallel increase in the release of the corresponding peptide in the culture medium. These findings suggest that the enhanced synthesis and release of endothelin-1 occurring in conditions of increased generation of TNF, may act as a modulatory factor that counteracts the hypotensive effect and the excessive platelet aggregation and adhesion induced by TNF.

scholarly journals Collagenase-3 Induction in Rat Lung Fibroblasts Requires the Combined Effects of Tumor Necrosis Factor-α and 12-Lipoxygenase Metabolites: A Model of Macrophage-induced, Fibroblast-driven Extracellular Matrix Remodeling during Inflammatory Lung Injury

1998 ◽  
Vol 9 (6) ◽  
pp. 1411-1424 ◽  
Author(s):  
Thomas J. Mariani ◽  
Stephanie Sandefur ◽  
Jill D. Roby ◽  
Richard A. Pierce
Keyword(s):  
Gene Expression ◽  
Conditioned Medium ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Rat Lung ◽  
Tnf Α ◽  
Factor Α ◽  
12 Lipoxygenase ◽  
Interstitial Collagenase ◽  
Necrosis Factor

The mechanisms responsible for the induction of matrix-degrading proteases during lung injury are ill defined. Macrophage-derived mediators are believed to play a role in regulating synthesis and turnover of extracellular matrix at sites of inflammation. We find a localized increase in the expression of the rat interstitial collagenase (MMP-13; collagenase-3) gene from fibroblastic cells directly adjacent to macrophages within silicotic rat lung granulomas. Conditioned medium from macrophages isolated from silicotic rat lungs was found to induce rat lung fibroblast interstitial collagenase gene expression. Conditioned medium from primary rat lung macrophages or J774 monocytic cells activated by particulates in vitro also induced interstitial collagenase gene expression. Tumor necrosis factor-α (TNF-α) alone did not induce interstitial collagenase expression in rat lung fibroblasts but did in rat skin fibroblasts, revealing tissue specificity in the regulation of this gene. The activity of the conditioned medium was found to be dependent on the combined effects of TNF-α and 12-lipoxygenase-derived arachidonic acid metabolites. The fibroblast response to this conditioned medium was dependent on de novo protein synthesis and involved the induction of nuclear activator protein-1 activity. These data reveal a novel requirement for macrophage-derived 12-lipoxygenase metabolites in lung fibroblast MMP induction and provide a mechanism for the induction of resident cell MMP gene expression during inflammatory lung processes.

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