PMID- 16507601
OWN - NLM
STAT- MEDLINE
DCOM- 20060912
LR  - 20161124
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 291
IP  - 2
DP  - 2006 Aug
TI  - Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor.
PG  - E315-22
AB  - 1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory 
      activity; however, the molecular mechanism remains poorly defined. Here we show 
      that the nuclear vitamin D receptor (VDR) is directly involved in the regulation 
      of NF-kappaB activation, a pathway essential for inflammatory response. In mouse 
      embryonic fibroblasts (MEFs) derived from VDR-/- mice, the basal level of kappaB 
      inhibitor (IkappaB) alpha protein was markedly decreased compared with VDR+/- 
      MEFs; however, degradation of IkappaBalpha and its phosphorylation in response to 
      TNF-alpha treatment or Salmonella infection were not altered in VDR-/- cells, 
      neither were the levels of IkappaB kinase-alpha and IkappaB kinase-beta proteins. 
      Consistent with IkappaBalpha reduction, p65 accumulation in the nucleus was 
      markedly increased in unstimulated VDR-/- cells. In addition, the physical 
      interaction between VDR and p65 was absent in VDR-/- MEFs, which may free p65 and 
      increase its activity. Consequently, these alterations combined led to a marked 
      increase in nuclear p65 DNA binding and NF-kappaB transcriptional activity; 
      consistently, induction of IL-6 by TNF-alpha or IL-1beta was much more robust in 
      VDR-/- than in VDR+/- cells, indicating that VDR-/- cells are more susceptible to 
      inflammatory stimulation. Therefore, cells lacking VDR appear to be more 
      proinflammatory due to the intrinsic high NF-kappaB activity. The reduction of 
      IkappaBalpha in VDR-/- MEFs may be partially explained by the lack of 
      VDR-mediated stabilization of IkappaBalpha by 1,25(OH)2D3. This is supported by 
      the observation that IkappaBalpha degradation induced by TNF-alpha was inhibited 
      by 1,25(OH)2D3 in VDR+/- cells, but not in VDR-/- cells. Taken together, these 
      data suggest that VDR plays an inhibitory role in the regulation of NF-kappaB 
      activation.
FAU - Sun, Jun
AU  - Sun J
AD  - Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
FAU - Kong, Juan
AU  - Kong J
FAU - Duan, Yingli
AU  - Duan Y
FAU - Szeto, Frances L
AU  - Szeto FL
FAU - Liao, Anne
AU  - Liao A
FAU - Madara, James L
AU  - Madara JL
FAU - Li, Yan Chun
AU  - Li YC
LA  - eng
GR  - DK-35932/DK/NIDDK NIH HHS/United States
GR  - DK-42086/DK/NIDDK NIH HHS/United States
GR  - DK-47662/DK/NIDDK NIH HHS/United States
GR  - DK-59327/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060228
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Nfkbia protein, rat)
RN  - 0 (Nucleocytoplasmic Transport Proteins)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (p65 oncofetal mRNA transport protein, rat)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 1406-16-2 (Vitamin D)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Fibroblasts/*metabolism
MH  - I-kappa B Proteins/*metabolism
MH  - Mice
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/*metabolism
MH  - Neoplasm Proteins/*metabolism
MH  - Nucleocytoplasmic Transport Proteins/*metabolism
MH  - Receptors, Calcitriol/*metabolism
MH  - Vitamin D/*metabolism
EDAT- 2006/03/02 09:00
MHDA- 2006/09/13 09:00
CRDT- 2006/03/02 09:00
PHST- 2006/03/02 09:00 [pubmed]
PHST- 2006/09/13 09:00 [medline]
PHST- 2006/03/02 09:00 [entrez]
AID - 00590.2005 [pii]
AID - 10.1152/ajpendo.00590.2005 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E315-22. doi: 
      10.1152/ajpendo.00590.2005. Epub 2006 Feb 28.