Signal transduction for formation/release of interleukin-8 caused by a PAR2-activating peptide in human lung epithelial cells

Moriyuki, Kazumi; Nagataki, Mami; Sekiguchi, Fumiko; Nishikawa, Hiroyuki; Kawabata, Atsufumi

doi:10.1016/j.regpep.2007.08.002

Cited by 16 publications

(12 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous studies have demonstrated that stimulation of PAR2 causes phosphorylation of all three MAP kinases, ERK, p38MAPK, and JNK, in A549 cells (18,19). The data from inhibition experiments in the present study suggest that the PAR2-triggered NF-κB activation is mainly mediated by the MEK / ERK pathway, but not p38MAPK or JNK (see Fig.…”

Section: Discussionsupporting

confidence: 58%

Proteinase-Activated Receptor-2–Triggered Prostaglandin E2 Release, but Not Cyclooxygenase-2 Upregulation, Requires Activation of the Phosphatidylinositol 3–Kinase / Akt / Nuclear Factor-κB Pathway in Human Alveolar Epithelial Cells

et al. 2009

Self Cite

View full text Add to dashboard Cite

Abstract. Proteinase-activated receptor-2 (PAR2) triggers upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) formation in human alveolar epithelial A549 cells. This COX-2 upregulation appears to involve the Src / epidermal growth factor (EGF) receptor / p38 MAP kinase (p38MAPK) pathway and also the cAMP-response element-binding protein (CREB) pathway. Here, we investigated the roles of nuclear factor-κB (NF-κB)-related signals in the PAR2-triggered PGE 2 release / COX-2 upregulation in A549 cells. The PAR2-triggered PGE 2 release was clearly blocked by an inhibitor of the NF-κB pathway. Stimulation of PAR2 actually caused phosphorylation of inhibitor-κB, an indicator of NF-κB activation, an effect being blocked by inhibitors of MEK, phosphatidylinositol 3-kinase (PI3-kinase), and Akt, but little or not by inhibitors of p38MAPK and JNK. Stimulation of PAR2 also caused phosphorylation of Akt, an effect suppressed by inhibitors of PI3-kinase and MEK. Nonetheless, the PAR2-triggered upregulation of COX-2 was resistant to inhibitors of NF-κB, PI3-kinase, and Akt, but was attenuated by inhibitors of MEK and JNK. Stimulation of PAR2 induced phosphorylation of CREB, an effect abolished by an inhibitor of MEK but not inhibitors of p38MAPK and EGF receptor. These findings demonstrate that the MEK / ERK / PI3-kinase / Akt / NF-κB pathway is involved in PAR2-triggered PGE 2 formation, but not upregulation of COX-2 that is dependent on activation of ERK /CREB and JNK in addition to p38MAPK.

show abstract

Section: Discussionsupporting

confidence: 58%

Proteinase-Activated Receptor-2–Triggered Prostaglandin E2 Release, but Not Cyclooxygenase-2 Upregulation, Requires Activation of the Phosphatidylinositol 3–Kinase / Akt / Nuclear Factor-κB Pathway in Human Alveolar Epithelial Cells

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, Ando et al demonstrated that PAR 4 -mediated EGFR signalling plays a role in alveolar epithelial-mesenchymal transition (EMT), an important mechanism in pulmonary lung fibrosis [108]. In addition, EGFR activation has been found to be involved in PAR 2 -triggered signal transduction pathways that contribute to a post-transcriptional process for the release of IL-8 in human lung epithelial cells [109]. Thus, PAR activation with or without a transactivation of the EGFR is of importance in the pathophysiology of the lung.…”

Section: Par-triggered Receptor Transactivation: Pathophysiological Imentioning

confidence: 99%

“…The use of PAR 4 -, PAR 2 -, and/or PAR 1 -specific antagonists along with EGFR blockers may be considered here since (1) PAR 4 -mediated EGFR signalling promotes alveolar epithelial-mesenchymal transition, an important mechanism in pulmonary lung fibrosis [108], (2) PAR 2 -mediated EGFR activation promotes the release of profibrotic IL-8 in human lung epithelial cells [109], and (3) PAR 1 -mediated enhancement of αVβ6-dependent TGF-β activation results in activation of the ALK5 kinase [50] and consequently profibrotic TGF-β responses. Since an overstimulation of PAR 1 -mediated enhancement of αVβ6-dependent TGF-β activation promotes acute lung injury [61], a combined therapy with PAR 1 antagonists and TGF-β signalling inhibitors (see below) may be considered.…”

Section: Proteinase-activated Receptor Signalling Receptor Dimerizatmentioning

confidence: 99%

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

et al. 2013

View full text Add to dashboard Cite

Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.

show abstract

“…GPCRs coupled to the G q family of Gα proteins have the capability in some cell types to stimulate cytokine gene expression through the activation of the proinflammatory transcription factor NF-κB. Examples of this include Tacr1 [8], PAF receptor [15], PAR-2 [16], and the BK B2 receptor [17]. Because most such studies were performed in transformed cells lines and/or with overexpressed receptors, we examined in the current experiments the ability of these GPCRs to induce chemokine expression in primary lung cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, treatment of A549 cells with BK led to NF-κB activation mediated by the BK B2 receptor through a Ras/Raf/Erk-dependent pathway [17]. PAR-2-induced upregulation of IL-8 production in A549 cells was dependent on PKC, MEK, and tyrosine kinase activity [16]. SP-induced upregulation of NF-κB in human endothelial cells was dependent on intracellular calcium release [30].…”

Section: Discussionmentioning

confidence: 99%

Common Pathways for Activation of Proinflammatory Gene Expression by G Protein–coupled Receptors in Primary Lung Epithelial and Endothelial Cells

Chang

Chen

Schlueter

et al. 2009

Experimental Lung Research

View full text Add to dashboard Cite

Acute lung injury is associated with an inflammatory response resulting from the action of multiple mediators. Many proinflammatory mediators released during lung injury exert effects by binding to G protein-coupled receptors (GPCRs). Our earlier studies showed that substance P (SP), a ligand for the tachykinin 1 receptor, induced NF-κB activation and IL-8 upregulation through a Gq-dependent pathway. Here we extend these findings by examining effects of multiple ligands for Gq-coupled GPCRs in primary human small airway epithelial cells (SAECs) and rat lung microvessel endothelial cells (RLMVECs). SP, bradykinin, protease activated receptor 2 agonist, and platelet activating factor (PAF) stimulated IL-8 production in SAECs, whereas only SP and PAF upregulated CINC-1 (a rat IL-8 homolog) in RLMVECs. Using signaling inhibitors, we investigated PAF-induced IL-8 expression and SP-induced CINC-1 expression in primary cells. Signaling cascades were similar in SAECs and RLMVECs and involved phospholipase C/calcium/PKC and Ras/Raf/Erk pathways. In addition, the tyrosine kinase inhibitor AG 17 and the proteasome inhibitor MG132 significantly reduced IL-8 and CINC-1 expression induced by GPCR ligands. The results demonstrate a common signaling pathway in primary lung epithelial and endothelial cells, suggesting a generalized mechanism for the induction of proinflammatory gene expression by Gq-coupled GPCRs following lung injury.

show abstract

Signal transduction for formation/release of interleukin-8 caused by a PAR2-activating peptide in human lung epithelial cells

Cited by 16 publications

References 32 publications

Proteinase-Activated Receptor-2–Triggered Prostaglandin E2 Release, but Not Cyclooxygenase-2 Upregulation, Requires Activation of the Phosphatidylinositol 3–Kinase / Akt / Nuclear Factor-κB Pathway in Human Alveolar Epithelial Cells

Proteinase-Activated Receptor-2–Triggered Prostaglandin E2 Release, but Not Cyclooxygenase-2 Upregulation, Requires Activation of the Phosphatidylinositol 3–Kinase / Akt / Nuclear Factor-κB Pathway in Human Alveolar Epithelial Cells

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

Common Pathways for Activation of Proinflammatory Gene Expression by G Protein–coupled Receptors in Primary Lung Epithelial and Endothelial Cells

Contact Info

Product

Resources

About