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 language | English |
|---|---|
| Pages (from-to) | 252-262 |
| Number of pages | 11 |
| Journal | Journal of Clinical Investigation |
| Volume | 101 |
| Issue number | 1 |
| Publication status | Published - Jan 1 1998 |
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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 journal › Article
}
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 -