Interleukin-6 Production by Endothelial Cells via Stimulation of Protease-Activated Receptors Is Amplified by Endotoxin and Tumor Necrosis Factor-α

Chi, Luqi; Li, Yuai; Stehno‐Bittel, Lisa; Gao, Jianjun; Morrison, David C.; Stechschulte, Daniel J.; Dileepan, Kottarappat N.

doi:10.1089/107999001750169871

Cited by 126 publications

(100 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…39 Others have reported that activation of PAR induced detectable levels of IL-6 production in a dose-dependent fashion. 40 Our results indicated that PAR4 mRNA was up-regulated in response to all three stimuli. As mast cells and tryptase are common features of IC, it is tempting to suggest that tryptase generated during the mast cell degranulation along with an up-regulation of PAR4 may contribute to abnormal neurotransmission and motility in the inflamed bladder.…”

Section: Par and Tryptasementioning

confidence: 52%

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Saban

Nguyen

Hammond

et al. 2002

The American Journal of Pathology

110

View full text Add to dashboard Cite

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and isClinical and animal models of acute and chronic urinary bladder inflammation have provided several lines of evidence suggesting a central role of mast cells, sensory nerves, and neurokinin (NK)-1 receptors. Fundamental work regarding the participation of sensory nerves and mast cells in cystitis provides indirect evidence, such as increased numbers of mast cells in the detrusor and submucosa, and morphological evidence of mast cell activation and degranulation. [1][2][3][4] In addition, the extensive tissue remodeling seen in some clinical forms of bladder inflammation such as interstitial cystitis, 4 along with increased urinary levels of histamine and tryptase 5 suggest a role for mast cells. Because both mast cells 6 -8 and NK-1 receptors are increased in bladder biopsies of interstitial cystitis (IC) patients, 9,10 it is tempting to propose a role for sensory peptides-mast cell communication in the pathogenesis of this disorder.Experimentally, we have used classical morphometric analysis and microarray technology to determine the role of mast cells, NK-1 receptors, and bacterial toxins in animal models of cystitis. Time-course experiments indicated early and late genes involved in bladder inflammatory responses. 11 The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R Ϫ/Ϫ ) allowed us to propose a mandatory role of SP receptors in cystitis. 12 We also determined genes that depend on the presence of tissue mast cells for their expression by comparing inflammatory responses in mast cell-deficient (Kit W /

show abstract

Section: Par and Tryptasementioning

confidence: 52%

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Saban

Nguyen

Hammond

et al. 2002

The American Journal of Pathology

110

View full text Add to dashboard Cite

show abstract

“…Increasing interest is now focused on the role of COX-2 and prostanoid homeostasis in the pathogenesis of atherosclerosis (21). Previous reports from our laboratory have documented the ability of mast cell proteases and histamine to interact with endothelial cells and enhance inflammatory responses, as determined by the production of IL-6 and IL-8 (9,22,23) and expression of TLR2 and TLR4 (16). In the present study, we demonstrate that histamine, acting through H 1 R, selectively induces the expression of functionally active COX-2 and stimulates the production of PGI 2 and PGE 2 in HCAEC.…”

Section: Discussionmentioning

confidence: 99%

Histamine Directly and Synergistically with Lipopolysaccharide Stimulates Cyclooxygenase-2 Expression and Prostaglandin I2 and E2 Production in Human Coronary Artery Endothelial Cells

Tan

Essengue

Talreja

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Although histamine plays an essential role in inflammation, its influence on cyclooxygenases (COX) and prostanoid homeostasis is not well understood. In this study, we investigated the effects of histamine on the expression of COX-1 and COX-2 and determined their contribution to the production of PGE2, prostacyclin (PGI2), and thromboxane A2 in human coronary artery endothelial cells (HCAEC). Incubation of HCAEC monolayers with histamine resulted in marked increases in the expression of COX-2 and production of PGI2 and PGE2 with no significant change in the expression of COX-1. Histamine-induced increases in PGI2 and PGE2 production were due to increased expression and function of COX-2 because gene silencing by small interfering RNA or inhibition of the catalytic activity by a COX-2 inhibitor blocked prostanoid production. The effects of histamine on COX-2 expression and prostanoid production were mediated through H1 receptors. In addition to the direct effect, histamine was found to amplify LPS-stimulated COX-2 expression and PGE2 and PGI2 production. In contrast, histamine did not stimulate thromboxane A2 production in resting or LPS-activated HCAEC. Histamine-induced increases in the production of PGE2 and PGI2 were associated with increased expression of mRNA encoding PGE2 and PGI2 synthases. The physiological role of histamine on the regulation of COX-2 expression in the vasculature is indicated by the findings that the expression of COX-2 mRNA, but not COX-1 mRNA, was markedly reduced in the aortic tissues of histidine decarboxylase null mice. Thus, histamine plays an important role in the regulation of COX-2 expression and prostanoid homeostasis in vascular endothelium.

show abstract

“…Indeed, several studies have investigated the possible connection between PAR 2 -and TLR4-mediated signaling pathways. For example, concurrent activation of PAR 2 and TLR4 by PAR 2 AP and LPS, respectively, amplifies NF-B activation and IL-6 production in endothelial cells (37). In contrast, the inflammatory response induced by Aspergillus infection involves TLR4-mediated suppression of PAR 2 signaling (36).…”

Section: Ap-inducible Nf-b Reporter Activation That Was Protein Synthmentioning

confidence: 99%

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Rallabhandi

Nhu

Toshchakov

et al. 2008

Journal of Biological Chemistry

135

149

View full text Add to dashboard Cite

Proteinase-activated receptor 2 (PAR 2 ), a seven-transmembrane G protein-coupled receptor, is activated at inflammatory sites by proteolytic cleavage of its extracellular N terminus by trypsin-like enzymes, exposing a tethered, receptor-activating ligand. Synthetic agonist peptides (AP) that share the tethered ligand sequence also activate PAR 2 , often measured by Ca 2؉ release. PAR 2 contributes to inflammation through activation of NF-B-regulated genes; however, the mechanism by which this occurs is unknown. Overexpression of human PAR 2 in HEK293T cells resulted in concentration-dependent, PAR 2 AP-inducible NF-B reporter activation that was protein synthesis-independent, yet blocked by inhibitors that uncouple G i proteins or sequester intracellular Ca 2؉ . Because previous studies described synergistic PAR 2 -and TLR4-mediated cytokine production, we hypothesized that PAR 2 and TLR4 might interact at the level of signaling. In the absence of TLR4, PAR 2 -induced NF-B activity was inhibited by dominant negative (DN)-TRIF or DN-TRAM constructs, but not by DN-MyD88, findings confirmed using cell-permeable, adapter-specific BB loop blocking peptides. Co-expression of TLR4/MD-2/CD14 with PAR 2 in HEK293T cells led to a synergistic increase in AP-induced NF-B signaling that was MyD88-dependent and required a functional TLR4, despite the fact that AP exhibited no TLR4 agonist activity. Co-immunoprecipitation of PAR 2 and TLR4 revealed a physical association that was AP-dependent. The response to AP or lipopolysaccharide was significantly diminished in TLR4 ؊/؊ and PAR 2 ؊/؊ macrophages, respectively, and SW620 colonic epithelial cells exhibited synergistic responses to co-stimulation with AP and lipopolysaccharide. Our data suggest a unique interaction between two distinct innate immune response receptors and support a novel paradigm of receptor cooperativity in inflammatory responses.

show abstract

Interleukin-6 Production by Endothelial Cells via Stimulation of Protease-Activated Receptors Is Amplified by Endotoxin and Tumor Necrosis Factor-α

Cited by 126 publications

References 41 publications

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

Histamine Directly and Synergistically with Lipopolysaccharide Stimulates Cyclooxygenase-2 Expression and Prostaglandin I2 and E2 Production in Human Coronary Artery Endothelial Cells

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Contact Info

Product

Resources

About