PMID- 23696902
OWN - NLM
STAT- MEDLINE
DCOM- 20131223
LR  - 20240313
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 5
DP  - 2013
TI  - CD69 is a TGF-beta/1alpha,25-dihydroxyvitamin D3 target gene in monocytes.
PG  - e64635
LID - 10.1371/journal.pone.0064635 [doi]
LID - e64635
AB  - CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. 
      In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in 
      which the leukotrienes, a class of highly potent inflammatory mediators, are 
      produced. However, regarding CD69 gene expression and its regulatory mechanisms 
      in monocytes, only scarce data are available. Here, we report that CD69 mRNA 
      expression, analogous to that of 5-lipoxygenase, is induced by the physiologic 
      stimuli transforming growth factor-beta (TGF-beta) and 1alpha,25-dihydroxyvitamin D3 
      (1alpha,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed 
      that the effect was specific for monocytes. CD69 expression levels were increased 
      in a concentration-dependent manner, and kinetic analysis revealed a rapid onset 
      of mRNA expression, indicating that CD69 is a primary TGF-beta/1alpha,25(OH)2D3 target 
      gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo 
      transcription was initiated and proximal and distal parts were induced 
      concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or  approximately 2.3 kb 
      promoter fragments by TGF-beta and 1alpha,25(OH)2D3 could be observed in transient 
      reporter assays for CD69. Analysis of mRNA stability using a transcription 
      inhibitor and a 3'UTR reporter construct showed that TGF-beta and 1alpha,25(OH)2D3 do 
      not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly 
      demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on 
      Smad3. Comparative studies with different inhibitors for mitogen activated 
      protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene 
      regulation, whereas 5-lipoxygenase gene expression was only partly affected. 
      Mechanistically, we found evidence that CD69 gene upregulation depends on 
      TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene 
      expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by 
      the physiologic stimuli TGF-beta and 1alpha,25(OH)2D3 on mRNA level, although different 
      mechanisms account for the upregulation of each gene.
FAU - Wobke, Thea K
AU  - Wobke TK
AD  - Institute of Pharmaceutical Chemistry/ZAFES (Zentrum fur Arzneimittelforschung, 
      Entwicklung und Sicherheit), Goethe-University, Frankfurt am Main, Germany.
FAU - von Knethen, Andreas
AU  - von Knethen A
FAU - Steinhilber, Dieter
AU  - Steinhilber D
FAU - Sorg, Bernd L
AU  - Sorg BL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130516
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, Differentiation, T-Lymphocyte)
RN  - 0 (CD69 antigen)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (dihydroxy-vitamin D3)
RN  - 1406-16-2 (Vitamin D)
SB  - IM
EIN - PLoS One. 2014;9(1). doi:10.1371/annotation/b0f3fd01-7aad-498d-a104-d64d1f8deb29
MH  - Antigens, CD/genetics/*metabolism
MH  - Antigens, Differentiation, T-Lymphocyte/genetics/*metabolism
MH  - Blotting, Western
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Humans
MH  - Lectins, C-Type/genetics/*metabolism
MH  - Monocytes/*drug effects/*metabolism
MH  - Polymerase Chain Reaction
MH  - Transforming Growth Factor beta/*pharmacology
MH  - Vitamin D/*analogs & derivatives/pharmacology
PMC - PMC3655964
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/05/23 06:00
MHDA- 2013/12/24 06:00
PMCR- 2013/05/16
CRDT- 2013/05/23 06:00
PHST- 2012/11/21 00:00 [received]
PHST- 2013/04/16 00:00 [accepted]
PHST- 2013/05/23 06:00 [entrez]
PHST- 2013/05/23 06:00 [pubmed]
PHST- 2013/12/24 06:00 [medline]
PHST- 2013/05/16 00:00 [pmc-release]
AID - PONE-D-12-36549 [pii]
AID - 10.1371/journal.pone.0064635 [doi]
PST - epublish
SO  - PLoS One. 2013 May 16;8(5):e64635. doi: 10.1371/journal.pone.0064635. Print 2013.