Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-κb transcription factors

Youqi Han, Marschall S. Runge, Allan R. Brasier

Research output: Contribution to journalArticle

280 Citations (Scopus)

Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine expressed by angiotensin II (Ang II)-stimulated vascular smooth muscle cells (VSMCs) that functions as an autocrine growth factor. In this study, we analyze the mechanism for Ang II-inducible IL-6 expression in quiescent rat VSMCs. Stimulation with the Ang II agonist Sar1 Ang II (100 nmol/L) induced transcriptional expression of IL-6 mRNA transcripts of 1.8 and 2.4 kb. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, Sar1 Ang II treatment induced IL-6 transcription in a manner completely dependent on the nuclear factor-κB (NF-κB) motif. Sar1 Ang II induced cytoplasmic-to-nuclear translocation of the NF-κB subunits Rel A and NF- κB1 with parallel changes in DNA-binding activity in a biphasic manner, which produced an early peak at 15 minutes followed by a nadir 1 to 6 hours later and a later peak at 24 hours. The early phase of NF-κB translocation was dependent on weak simultaneous proteolysis of the IκBα and β inhibitors, whereas later translocation was associated with enhanced processing of the p105 precursor into the mature 50-kDa NF-κB1 form. Pretreatment with a potent inhibitor of IκBα proteolysis, TPCK, completely blocked Sar1 Ang IIAng II-induced NF-κB activation and induction of endogenous IL-6 gene expression, which indicated the essential role of NF- κB in mediating IL-6 expression. We conclude that Ang II is a pleiotropic regulator of the NF-κB transcription factor family and may be responsible for activating the expression of cytokine gene networks in VSMCs.

Original languageEnglish (US)
Pages (from-to)695-703
Number of pages9
JournalCirculation Research
Volume84
Issue number6
StatePublished - Apr 2 1999

Fingerprint

Vascular Smooth Muscle
Angiotensin II
Smooth Muscle Myocytes
Interleukin-6
Transcription Factors
Proteolysis
Tosylphenylalanyl Chloromethyl Ketone
Cytokines
Gene Regulatory Networks
Luciferases
Transfection
Intercellular Signaling Peptides and Proteins
Plasmids
Gene Expression
Messenger RNA
DNA

Keywords

  • Angiotensin II
  • Cytokine
  • Nuclear factor-κB
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-κb transcription factors. / Han, Youqi; Runge, Marschall S.; Brasier, Allan R.

In: Circulation Research, Vol. 84, No. 6, 02.04.1999, p. 695-703.

Research output: Contribution to journalArticle

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N2 - Interleukin-6 (IL-6) is a multifunctional cytokine expressed by angiotensin II (Ang II)-stimulated vascular smooth muscle cells (VSMCs) that functions as an autocrine growth factor. In this study, we analyze the mechanism for Ang II-inducible IL-6 expression in quiescent rat VSMCs. Stimulation with the Ang II agonist Sar1 Ang II (100 nmol/L) induced transcriptional expression of IL-6 mRNA transcripts of 1.8 and 2.4 kb. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, Sar1 Ang II treatment induced IL-6 transcription in a manner completely dependent on the nuclear factor-κB (NF-κB) motif. Sar1 Ang II induced cytoplasmic-to-nuclear translocation of the NF-κB subunits Rel A and NF- κB1 with parallel changes in DNA-binding activity in a biphasic manner, which produced an early peak at 15 minutes followed by a nadir 1 to 6 hours later and a later peak at 24 hours. The early phase of NF-κB translocation was dependent on weak simultaneous proteolysis of the IκBα and β inhibitors, whereas later translocation was associated with enhanced processing of the p105 precursor into the mature 50-kDa NF-κB1 form. Pretreatment with a potent inhibitor of IκBα proteolysis, TPCK, completely blocked Sar1 Ang IIAng II-induced NF-κB activation and induction of endogenous IL-6 gene expression, which indicated the essential role of NF- κB in mediating IL-6 expression. We conclude that Ang II is a pleiotropic regulator of the NF-κB transcription factor family and may be responsible for activating the expression of cytokine gene networks in VSMCs.

AB - Interleukin-6 (IL-6) is a multifunctional cytokine expressed by angiotensin II (Ang II)-stimulated vascular smooth muscle cells (VSMCs) that functions as an autocrine growth factor. In this study, we analyze the mechanism for Ang II-inducible IL-6 expression in quiescent rat VSMCs. Stimulation with the Ang II agonist Sar1 Ang II (100 nmol/L) induced transcriptional expression of IL-6 mRNA transcripts of 1.8 and 2.4 kb. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, Sar1 Ang II treatment induced IL-6 transcription in a manner completely dependent on the nuclear factor-κB (NF-κB) motif. Sar1 Ang II induced cytoplasmic-to-nuclear translocation of the NF-κB subunits Rel A and NF- κB1 with parallel changes in DNA-binding activity in a biphasic manner, which produced an early peak at 15 minutes followed by a nadir 1 to 6 hours later and a later peak at 24 hours. The early phase of NF-κB translocation was dependent on weak simultaneous proteolysis of the IκBα and β inhibitors, whereas later translocation was associated with enhanced processing of the p105 precursor into the mature 50-kDa NF-κB1 form. Pretreatment with a potent inhibitor of IκBα proteolysis, TPCK, completely blocked Sar1 Ang IIAng II-induced NF-κB activation and induction of endogenous IL-6 gene expression, which indicated the essential role of NF- κB in mediating IL-6 expression. We conclude that Ang II is a pleiotropic regulator of the NF-κB transcription factor family and may be responsible for activating the expression of cytokine gene networks in VSMCs.

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