Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-κB site on its promoter

Simeonidis, Simos; Castagliuolo, Ignazio; Pan, Amy; Liu, Jennifer; Wang, Chi-Chi; Mykoniatis, Andreas; Pasha, Asia; Valenick, Leyla; Sougioultzis, Stavros; Zhao, Dan; Pothoulakis, Charalabos

doi:10.1073/pnas.0530112100

Cited by 86 publications

(74 citation statements)

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“…Tacr1 has been shown in multiple contexts to be upregulated by noxious or stressful stimuli (2,33,35). Potential mechanisms underlying this regulation include NF-B and the neuropeptide calcitonin gene-related peptide (29,33). In the current study, Tacr1 expression was increased in cultured lung epithelial cells by transfection, so that signaling pathways specifically activated by Tacr1 could be dissected in the absence of additional intracellular events triggered by injury to the cells.…”

Section: Discussionmentioning

confidence: 99%

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G_q-dependent pathway

Rt¹,

Zou²,

Hoyle³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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The respiratory tract is innervated by irritant-responsive sensory nerves, which, on stimulation, release tachykinin neuropeptides in the lung. Tachykinins modulate inflammatory responses to injury by binding to tachykinin (neurokinin) receptors present on various pulmonary cell types. In the present study, the activation of the proinflammatory transcription factor NF-κB in lung epithelial cells was investigated as a mechanism by which tachykinins stimulate inflammatory processes. In A549 human lung epithelial cells transfected with the tachykinin-1 receptor (Tacr1), treatment with the Tacr1 ligand substance P (SP) resulted in NF-κB activation, as judged by transcription of an NF-κB-luciferase reporter gene and production of interleukin-8, a chemokine whose expression is upregulated by NF-κB. SP caused a dose-dependent activation of NF-κB that was inhibited by the selective Tacr1 antagonist RP67580. Tacr1 is a G protein-coupled receptor capable of activating both the Gq and Gs families of G proteins. Expression of inhibitory peptides and constitutively active G protein mutants revealed that Gq signaling was both necessary for Tacr1-induced NF-κB activation and sufficient for NF-κB activation in the absence of any other treatment. Treatment with pharmacological inhibitors to investigate events downstream of Gq revealed that Tacr1-induced NF-κB activation proceeded through an intracellular signaling pathway that was dependent on phospholipase C, calcium, Ras, Raf-1, MEK, Erk, and proteasome function. These results identify intracellular signaling mechanisms that underlie the proinflammatory effects of tachykinins, which previously have been implicated in lung injury and disease.

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Section: Discussionmentioning

confidence: 99%

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G_q-dependent pathway

Rt¹,

Zou²,

Hoyle³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…SP is expressed in enteric nerves (3), sensory neurons (4), and macrophages of the intestinal lamina propria (5). Binding of SP to its high-affinity neurokinin-1 receptor (NK-1R) modulates important intestinal responses, such as mucosal permeability (6), colonic motility (7), chloride secretion (8), and acute intestinal inflammation (9,10), via activation of the NF-B (11,12) and NF-B-regulated cytokines (13,14). SP-NK-1R interactions also induce proliferation of colonic epithelial as well as nonepithelial cells that involves activities of metalloproteinases and trans activation of the epidermal growth factor receptor (EGFR) (15,16).…”

mentioning

confidence: 99%

Substance P Stimulates Cyclooxygenase-2 and Prostaglandin E2 Expression through JAK-STAT Activation in Human Colonic Epithelial Cells

Koon

Zhao

Zhan

et al. 2006

The Journal of Immunology

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Substance P (SP) via its neurokinin-1 receptor (NK-1R) regulates several gastrointestinal functions. We previously reported that NK-1R-mediated chloride secretion in the colon involves formation of PG. PGE2 biosynthesis is controlled by cyclooxygenase-1 (COX-1) and COX-2, whose induction involves the STATs. In this study, we examined whether SP stimulates PGE2 production and COX-2 expression in human nontransformed NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) and identified the pathways involved in this response. SP exposure time and dose dependently induced an early (1-min) phosphorylation of JAK2, STAT3, and STAT5, followed by COX-2 expression and PGE2 production by 2 h. Pharmacologic experiments showed that PGE2 production is dependent on newly synthesized COX-2, but COX-1 protein. Inhibition of protein kinase Cθ (PKCθ), but not PKCε and PKCδ, significantly reduced SP-induced COX-2 up-regulation, and JAK2, STAT3, and STAT5 phosphorylation. Pharmacological blockade of JAK inhibited SP-induced JAK2, STAT3, and STAT5 phosphorylation; COX-2 expression; and PGE2 production. Transient transfection with JAK2 short-interferring RNA reduced COX-2 promoter activity and JAK2 phosphorylation, while RNA interference of STAT isoforms showed that STAT5 predominantly mediates SP-induced COX-2 promoter activity. Site-directed mutation of STAT binding sites on the COX-2 promoter completely abolished COX-2 promoter activity. Lastly, COX-2 expression was elevated in colon of mice during experimental colitis, and this effect was normalized by administration of the NK-1R antagonist CJ-12,255. Our results demonstrate that SP stimulates COX-2 expression and PGE2 production in human colonocytes via activation of the JAK2-STAT3/5 pathway.

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“…The proinflammatory responses to SP involve activation of the nuclear factor (NF)-B (Lieb et al, 1997;Azzolina et al, 2003) and secretion of proinflammatory cytokines, including interleukin-6, interleukin-8 (IL-8), and tumor necrosis factor ␣ (TNF␣) (Laurenzi et al, 1990;Derocq et al, 1996;Lieb et al, 1996;Castagliuolo et al, 1997;Fiebich et al, 2000;Zhao et al, 2002). Interestingly, proinflammatory cytokines and NF-B also regulate expression of NK-1R (Simeonidis et al, 2003).…”

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confidence: 99%

Substance P-Stimulated Interleukin-8 Expression in Human Colonic Epithelial Cells Involves Protein Kinase Cδ Activation

Koon¹,

Zhao²,

Zhan³

et al. 2005

J Pharmacol Exp Ther

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Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of nuclear factor B (NF-B)-driven proinflammatory cytokines from colonic epithelial cells. However, the signal transduction pathways by which SP-NK-1R interaction induces NF-B activation and interleukin-8 (IL-8) production are not clear. Here, we examined participation of protein kinase C (PKC) in SP-induced IL-8 production in human nontransformed NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells). SP (10 Ϫ7 M) induced an early (1 min) phosphorylation of the PKC isoforms PKC␦, PKC, and PKC⑀, followed by I-B kinase, IB␣, and p65 phosphorylation. Depletion of PKC by phorbol-12-myristate-13-acetate (10 M) blocked SP-induced IB␣ and p65 phosphorylation and IL-8 production. The PKC␦ inhibitor rottlerin at a low concentration (1 M), but not pseudosubstrate PKC and PKC⑀ inhibitors (10 M), significantly reduced IL-8 secretion. PKC␦ silencing by RNA interference reduced PKC␦ protein expression and SP-induced PKC␦ phosphorylation that was associated with diminished IL-8 promoter and NF-B luciferase activities in response to SP. Moreover, overexpression of wildtype PKC␦ increased SP-induced IL-8 promoter-and NF-Bdriven luciferase activities that were rottlerin-sensitive. We conclude that PKC␦ plays an important role in SP-induced proinflammatory signaling in human colonocytes.

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Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-κB site on its promoter

Abstract: We report here that human monocytic͞macrophage THP-1 cells express the neurokinin 1 receptor (NK-1R), and that exposure of these cells to the proinflammatory cytokine IL-1␤ increased the expression of the NK-1R gene at the mRNA and protein levels.

Cited by 86 publications

References 42 publications

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G_q-dependent pathway

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G_q-dependent pathway

Substance P Stimulates Cyclooxygenase-2 and Prostaglandin E2 Expression through JAK-STAT Activation in Human Colonic Epithelial Cells

Substance P-Stimulated Interleukin-8 Expression in Human Colonic Epithelial Cells Involves Protein Kinase Cδ Activation

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Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-κB site on its promoter

Abstract: We report here that human monocytic͞macrophage THP-1 cells express the neurokinin 1 receptor (NK-1R), and that exposure of these cells to the proinflammatory cytokine IL-1␤ increased the expression of the NK-1R gene at the mRNA and protein levels.

Cited by 86 publications

References 42 publications

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a Gq-dependent pathway

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a Gq-dependent pathway

Substance P Stimulates Cyclooxygenase-2 and Prostaglandin E2 Expression through JAK-STAT Activation in Human Colonic Epithelial Cells

Substance P-Stimulated Interleukin-8 Expression in Human Colonic Epithelial Cells Involves Protein Kinase Cδ Activation

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Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G_q-dependent pathway

Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G_q-dependent pathway