TNFα suppresses human colonic circular smooth muscle cell contractility by SP1- and NF-κB-mediated induction of ICAM-1

Konrad Pazdrak, Xuan-Zheng Shi, Sushil K. Sarna

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) receptors are expressed at low levels on human colonic circular smooth muscle cells (HCCSMCs) and their expression is increased in patients with Crohn's disease. We investigated the roles of transcription factors Sp1 and nuclear factor κ B (NF-κB) in the regulation of ICAM-1 expression on HCCSMCs and examined whether ICAM-1 expression mediates the suppression of contractility in response to TNFα. Methods: Experiments were performed on primary cultures of HCCSMCs and fresh human colonic circular muscle strips. Results: TNFα treatment of HCCSMCs induced rapid and prolonged accumulation of ICAM-1 messenger RNA (mRNA) and protein. NF-κB inhibition before, but not after, 1 hour of TNFα-stimulation blocked the expression of ICAM-1. TNFα significantly enhanced Sp1/DNA binding. Sp1 bound to the 3′ flanking region of a variant κB site in the -192/-172 region of ICAM-1 promoter. Mutation of this region abolished the response to TNFα. The treatment of HCCSMCs with Sp1 antisense oligonucleotides (ODNs) blocked the expression of ICAM-1, but sense ODNs had no effect. Protein kinase C ζ (PKCζ) inhibition before or 3 hours after stimulation with TNFα also blocked the expression of ICAM-1. TNFα treatment of circular muscle strips pretreated with ICAM-1 sense ODNs or control medium significantly reduced their response to acetylcholine, whereas pretreatment with antisense ODNs blocked this effect. Conclusions: The expression of ICAM-1 on HCCSMCs in response to TNFα is regulated by transcription factors Sp1 and NF-κB binding independently to the -192/-172 region of the ICAM-1 promoter. The expression of ICAM-1 plays a critical role in the suppression of cell contractility in response to TNFα.

Original languageEnglish (US)
Pages (from-to)1096-1109
Number of pages14
JournalGastroenterology
Volume127
Issue number4
DOIs
StatePublished - Oct 2004

Fingerprint

Intercellular Adhesion Molecule-1
Smooth Muscle Myocytes
Sp1 Transcription Factor
3' Flanking Region
Muscles
Antisense Oligonucleotides
Crohn Disease
Protein Kinase C
Acetylcholine
Therapeutics

ASJC Scopus subject areas

  • Gastroenterology

Cite this

TNFα suppresses human colonic circular smooth muscle cell contractility by SP1- and NF-κB-mediated induction of ICAM-1. / Pazdrak, Konrad; Shi, Xuan-Zheng; Sarna, Sushil K.

In: Gastroenterology, Vol. 127, No. 4, 10.2004, p. 1096-1109.

Research output: Contribution to journalArticle

@article{86eb236691f24859a3f34142d13dc178,
title = "TNFα suppresses human colonic circular smooth muscle cell contractility by SP1- and NF-κB-mediated induction of ICAM-1",
abstract = "Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) receptors are expressed at low levels on human colonic circular smooth muscle cells (HCCSMCs) and their expression is increased in patients with Crohn's disease. We investigated the roles of transcription factors Sp1 and nuclear factor κ B (NF-κB) in the regulation of ICAM-1 expression on HCCSMCs and examined whether ICAM-1 expression mediates the suppression of contractility in response to TNFα. Methods: Experiments were performed on primary cultures of HCCSMCs and fresh human colonic circular muscle strips. Results: TNFα treatment of HCCSMCs induced rapid and prolonged accumulation of ICAM-1 messenger RNA (mRNA) and protein. NF-κB inhibition before, but not after, 1 hour of TNFα-stimulation blocked the expression of ICAM-1. TNFα significantly enhanced Sp1/DNA binding. Sp1 bound to the 3′ flanking region of a variant κB site in the -192/-172 region of ICAM-1 promoter. Mutation of this region abolished the response to TNFα. The treatment of HCCSMCs with Sp1 antisense oligonucleotides (ODNs) blocked the expression of ICAM-1, but sense ODNs had no effect. Protein kinase C ζ (PKCζ) inhibition before or 3 hours after stimulation with TNFα also blocked the expression of ICAM-1. TNFα treatment of circular muscle strips pretreated with ICAM-1 sense ODNs or control medium significantly reduced their response to acetylcholine, whereas pretreatment with antisense ODNs blocked this effect. Conclusions: The expression of ICAM-1 on HCCSMCs in response to TNFα is regulated by transcription factors Sp1 and NF-κB binding independently to the -192/-172 region of the ICAM-1 promoter. The expression of ICAM-1 plays a critical role in the suppression of cell contractility in response to TNFα.",
author = "Konrad Pazdrak and Xuan-Zheng Shi and Sarna, {Sushil K.}",
year = "2004",
month = "10",
doi = "10.1053/j.gastro.2004.07.008",
language = "English (US)",
volume = "127",
pages = "1096--1109",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - TNFα suppresses human colonic circular smooth muscle cell contractility by SP1- and NF-κB-mediated induction of ICAM-1

AU - Pazdrak, Konrad

AU - Shi, Xuan-Zheng

AU - Sarna, Sushil K.

PY - 2004/10

Y1 - 2004/10

N2 - Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) receptors are expressed at low levels on human colonic circular smooth muscle cells (HCCSMCs) and their expression is increased in patients with Crohn's disease. We investigated the roles of transcription factors Sp1 and nuclear factor κ B (NF-κB) in the regulation of ICAM-1 expression on HCCSMCs and examined whether ICAM-1 expression mediates the suppression of contractility in response to TNFα. Methods: Experiments were performed on primary cultures of HCCSMCs and fresh human colonic circular muscle strips. Results: TNFα treatment of HCCSMCs induced rapid and prolonged accumulation of ICAM-1 messenger RNA (mRNA) and protein. NF-κB inhibition before, but not after, 1 hour of TNFα-stimulation blocked the expression of ICAM-1. TNFα significantly enhanced Sp1/DNA binding. Sp1 bound to the 3′ flanking region of a variant κB site in the -192/-172 region of ICAM-1 promoter. Mutation of this region abolished the response to TNFα. The treatment of HCCSMCs with Sp1 antisense oligonucleotides (ODNs) blocked the expression of ICAM-1, but sense ODNs had no effect. Protein kinase C ζ (PKCζ) inhibition before or 3 hours after stimulation with TNFα also blocked the expression of ICAM-1. TNFα treatment of circular muscle strips pretreated with ICAM-1 sense ODNs or control medium significantly reduced their response to acetylcholine, whereas pretreatment with antisense ODNs blocked this effect. Conclusions: The expression of ICAM-1 on HCCSMCs in response to TNFα is regulated by transcription factors Sp1 and NF-κB binding independently to the -192/-172 region of the ICAM-1 promoter. The expression of ICAM-1 plays a critical role in the suppression of cell contractility in response to TNFα.

AB - Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) receptors are expressed at low levels on human colonic circular smooth muscle cells (HCCSMCs) and their expression is increased in patients with Crohn's disease. We investigated the roles of transcription factors Sp1 and nuclear factor κ B (NF-κB) in the regulation of ICAM-1 expression on HCCSMCs and examined whether ICAM-1 expression mediates the suppression of contractility in response to TNFα. Methods: Experiments were performed on primary cultures of HCCSMCs and fresh human colonic circular muscle strips. Results: TNFα treatment of HCCSMCs induced rapid and prolonged accumulation of ICAM-1 messenger RNA (mRNA) and protein. NF-κB inhibition before, but not after, 1 hour of TNFα-stimulation blocked the expression of ICAM-1. TNFα significantly enhanced Sp1/DNA binding. Sp1 bound to the 3′ flanking region of a variant κB site in the -192/-172 region of ICAM-1 promoter. Mutation of this region abolished the response to TNFα. The treatment of HCCSMCs with Sp1 antisense oligonucleotides (ODNs) blocked the expression of ICAM-1, but sense ODNs had no effect. Protein kinase C ζ (PKCζ) inhibition before or 3 hours after stimulation with TNFα also blocked the expression of ICAM-1. TNFα treatment of circular muscle strips pretreated with ICAM-1 sense ODNs or control medium significantly reduced their response to acetylcholine, whereas pretreatment with antisense ODNs blocked this effect. Conclusions: The expression of ICAM-1 on HCCSMCs in response to TNFα is regulated by transcription factors Sp1 and NF-κB binding independently to the -192/-172 region of the ICAM-1 promoter. The expression of ICAM-1 plays a critical role in the suppression of cell contractility in response to TNFα.

UR - http://www.scopus.com/inward/record.url?scp=5144225951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=5144225951&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2004.07.008

DO - 10.1053/j.gastro.2004.07.008

M3 - Article

C2 - 15480988

AN - SCOPUS:5144225951

VL - 127

SP - 1096

EP - 1109

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -