Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene

Daniele D'Ambrosio, Marco Cippitelli, Maria Gabriella Cocciolo, Daniela Mazzeo, Pietro Di Lucia, Rosmarie Lang, Francesco Sinigaglia, Paola Panina-Bordignon

Research output: Contribution to journalArticle

Abstract

Interleukin 12 (IL-12), produced by myelomonocytic cells, plays a pivotal role in the development of T helper 1 (Th1) cells, which are involved in the pathogenesis of chronic inflammatory autoimmune disorders. 1,25- Dihydroxyvitamin D3 [1,25(OH)2D3] inhibits IL-12 production by activated macrophages and dendritic cells, thus providing a novel interpretation to its immunosuppressive properties. 1,25(OH)2D3 significantly inhibits mRNA expression for both IL-12 p35 and p40 subunits acting at the transcriptional level. The effect of 1,25(OH)2D3 on p40 promoter activation was analyzed by cotransfecting monocytic RAW264.7 cells with p40 promoter/reporter constructs and expression vectors for vitamin D3 receptor (VDR) and/or retinoid X receptor (RXRα). We observed transcriptional repression of the p40 gene by 1,25(OH)2D3, which required coexpression of VDR with RXR and an intact VDR DNA-binding domain. The repressive effect maps to a region in the p40 promoter containing a binding site for NF-κB (p40-κB). Deletion of the p40- κB site abrogates part of the inhibitory effect on the p40 promoter, confirming the functional relevance of this site. Activation of monocytic THP-1 cells in the presence of 1,25(OH)2D3 results in reduced binding to the p40-κB site. Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-κB activation and binding to the p40-κB sequence.

Original languageEnglish
Pages (from-to)252-262
Number of pages11
JournalJournal of Clinical Investigation
Volume101
Issue number1
Publication statusPublished - Jan 1 1998

Fingerprint

Calcitriol
Interleukin-12
Down-Regulation
Genes
Calcitriol Receptors
Retinoid X Receptors
Interleukin-12 Subunit p35
Interleukin-12 Subunit p40
adjuvant P40
Th1 Cells
Immunosuppressive Agents
Dendritic Cells
Macrophages
Binding Sites
Messenger RNA
DNA

Keywords

  • Antiinflammatory drug
  • Autoimmunity
  • NF-κB
  • T helper
  • VDR

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. / D'Ambrosio, Daniele; Cippitelli, Marco; Cocciolo, Maria Gabriella; Mazzeo, Daniela; Di Lucia, Pietro; Lang, Rosmarie; Sinigaglia, Francesco; Panina-Bordignon, Paola.

In: Journal of Clinical Investigation, Vol. 101, No. 1, 01.01.1998, p. 252-262.

Research output: Contribution to journalArticle

D'Ambrosio, D, Cippitelli, M, Cocciolo, MG, Mazzeo, D, Di Lucia, P, Lang, R, Sinigaglia, F & Panina-Bordignon, P 1998, 'Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene', Journal of Clinical Investigation, vol. 101, no. 1, pp. 252-262.
D'Ambrosio, Daniele ; Cippitelli, Marco ; Cocciolo, Maria Gabriella ; Mazzeo, Daniela ; Di Lucia, Pietro ; Lang, Rosmarie ; Sinigaglia, Francesco ; Panina-Bordignon, Paola. / Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. In: Journal of Clinical Investigation. 1998 ; Vol. 101, No. 1. pp. 252-262.
@article{c32762c5722a4b049a9c5db99afa411f,
title = "Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene",
abstract = "Interleukin 12 (IL-12), produced by myelomonocytic cells, plays a pivotal role in the development of T helper 1 (Th1) cells, which are involved in the pathogenesis of chronic inflammatory autoimmune disorders. 1,25- Dihydroxyvitamin D3 [1,25(OH)2D3] inhibits IL-12 production by activated macrophages and dendritic cells, thus providing a novel interpretation to its immunosuppressive properties. 1,25(OH)2D3 significantly inhibits mRNA expression for both IL-12 p35 and p40 subunits acting at the transcriptional level. The effect of 1,25(OH)2D3 on p40 promoter activation was analyzed by cotransfecting monocytic RAW264.7 cells with p40 promoter/reporter constructs and expression vectors for vitamin D3 receptor (VDR) and/or retinoid X receptor (RXRα). We observed transcriptional repression of the p40 gene by 1,25(OH)2D3, which required coexpression of VDR with RXR and an intact VDR DNA-binding domain. The repressive effect maps to a region in the p40 promoter containing a binding site for NF-κB (p40-κB). Deletion of the p40- κB site abrogates part of the inhibitory effect on the p40 promoter, confirming the functional relevance of this site. Activation of monocytic THP-1 cells in the presence of 1,25(OH)2D3 results in reduced binding to the p40-κB site. Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-κB activation and binding to the p40-κB sequence.",
keywords = "Antiinflammatory drug, Autoimmunity, NF-κB, T helper, VDR",
author = "Daniele D'Ambrosio and Marco Cippitelli and Cocciolo, {Maria Gabriella} and Daniela Mazzeo and {Di Lucia}, Pietro and Rosmarie Lang and Francesco Sinigaglia and Paola Panina-Bordignon",
year = "1998",
month = "1",
day = "1",
language = "English",
volume = "101",
pages = "252--262",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene

AU - D'Ambrosio, Daniele

AU - Cippitelli, Marco

AU - Cocciolo, Maria Gabriella

AU - Mazzeo, Daniela

AU - Di Lucia, Pietro

AU - Lang, Rosmarie

AU - Sinigaglia, Francesco

AU - Panina-Bordignon, Paola

PY - 1998/1/1

Y1 - 1998/1/1

N2 - Interleukin 12 (IL-12), produced by myelomonocytic cells, plays a pivotal role in the development of T helper 1 (Th1) cells, which are involved in the pathogenesis of chronic inflammatory autoimmune disorders. 1,25- Dihydroxyvitamin D3 [1,25(OH)2D3] inhibits IL-12 production by activated macrophages and dendritic cells, thus providing a novel interpretation to its immunosuppressive properties. 1,25(OH)2D3 significantly inhibits mRNA expression for both IL-12 p35 and p40 subunits acting at the transcriptional level. The effect of 1,25(OH)2D3 on p40 promoter activation was analyzed by cotransfecting monocytic RAW264.7 cells with p40 promoter/reporter constructs and expression vectors for vitamin D3 receptor (VDR) and/or retinoid X receptor (RXRα). We observed transcriptional repression of the p40 gene by 1,25(OH)2D3, which required coexpression of VDR with RXR and an intact VDR DNA-binding domain. The repressive effect maps to a region in the p40 promoter containing a binding site for NF-κB (p40-κB). Deletion of the p40- κB site abrogates part of the inhibitory effect on the p40 promoter, confirming the functional relevance of this site. Activation of monocytic THP-1 cells in the presence of 1,25(OH)2D3 results in reduced binding to the p40-κB site. Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-κB activation and binding to the p40-κB sequence.

AB - Interleukin 12 (IL-12), produced by myelomonocytic cells, plays a pivotal role in the development of T helper 1 (Th1) cells, which are involved in the pathogenesis of chronic inflammatory autoimmune disorders. 1,25- Dihydroxyvitamin D3 [1,25(OH)2D3] inhibits IL-12 production by activated macrophages and dendritic cells, thus providing a novel interpretation to its immunosuppressive properties. 1,25(OH)2D3 significantly inhibits mRNA expression for both IL-12 p35 and p40 subunits acting at the transcriptional level. The effect of 1,25(OH)2D3 on p40 promoter activation was analyzed by cotransfecting monocytic RAW264.7 cells with p40 promoter/reporter constructs and expression vectors for vitamin D3 receptor (VDR) and/or retinoid X receptor (RXRα). We observed transcriptional repression of the p40 gene by 1,25(OH)2D3, which required coexpression of VDR with RXR and an intact VDR DNA-binding domain. The repressive effect maps to a region in the p40 promoter containing a binding site for NF-κB (p40-κB). Deletion of the p40- κB site abrogates part of the inhibitory effect on the p40 promoter, confirming the functional relevance of this site. Activation of monocytic THP-1 cells in the presence of 1,25(OH)2D3 results in reduced binding to the p40-κB site. Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-κB activation and binding to the p40-κB sequence.

KW - Antiinflammatory drug

KW - Autoimmunity

KW - NF-κB

KW - T helper

KW - VDR

UR - http://www.scopus.com/inward/record.url?scp=0031974910&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031974910&partnerID=8YFLogxK

M3 - Article

C2 - 9421488

AN - SCOPUS:0031974910

VL - 101

SP - 252

EP - 262

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -