PMID- 20649565
OWN - NLM
STAT- MEDLINE
DCOM- 20101130
LR  - 20211020
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 160
IP  - 7
DP  - 2010 Aug
TI  - In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production 
      of the chemokine CCL2, stimulated by tumour necrosis factor-alpha.
PG  - 1611-20
LID - 10.1111/j.1476-5381.2010.00837.x [doi]
AB  - BACKGROUND AND PURPOSE: Renal fibroblasts play a pivotal role in the development 
      of tubulointerstitial fibrosis, a condition highly predictive of progression 
      towards end-stage renal disease. The present study investigated the 
      anti-mitogenic and anti-inflammatory effects of an inhibitor of inosine 
      monophosphate dehydrogenase, mycophenolic acid (MPA) and the mechanisms 
      underlying its action in normal rat kidney fibroblasts (49F cells). EXPERIMENTAL 
      APPROACH: Proliferation of 49F cells was studied by tetrazole 3-(4, 
      5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide (MTT) test, 
      bromodeoxyuridine incorporation and flow cytometry. The cyclins, tumour 
      suppressor genes and phospho-mitogen-activated protein kinases (MAPKs) were 
      semiquantified by immunoblotting. Apoptosis was measured by quantifying the 
      fragmented DNA and the activity of caspase 3. The monocyte chemokine CCL2 was 
      measured by ELISA. The mRNA expression of CCL2 was measured by real-time PCR. KEY 
      RESULTS: Mycophenolic acid dose-dependently inhibited steady-state proliferation 
      of 49F cells by up-regulation of p21, p27 and p53, in association with a decrease 
      in cyclins D2 and E. Treatment with MPA also triggered apoptosis of 49F cells by 
      activating the caspase 3 cascade. Furthermore, MPA attenuated tumour necrosis 
      factor-alpha-induced CCL2 expression through down-regulation of p38 MAPK, but not 
      that of ERK1/2 or JNK. CONCLUSIONS AND IMPLICATIONS: The anti-mitogenic and 
      anti-inflammatory effects of MPA were mediated by up-regulation of cell cycle 
      inhibitors and pro-apoptotic signals, and by suppression of p38 MAPK pathway 
      respectively. This dual effect of MPA may form the rationale for animal or 
      clinical trials for the treatment of fibrotic renal diseases.
FAU - Chang, Hong-Wei
AU  - Chang HW
AD  - Renal Division, Department of Internal Medicine, National Taiwan University 
      Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
FAU - Wu, Vin-Cent
AU  - Wu VC
FAU - Wu, Kwan-Dun
AU  - Wu KD
FAU - Huang, Hong-Yu
AU  - Huang HY
FAU - Hsieh, Bor-Shen
AU  - Hsieh BS
FAU - Chen, Yung-Ming
AU  - Chen YM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - HU9DX48N0T (Mycophenolic Acid)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Caspase 3/metabolism
MH  - Cell Culture Techniques
MH  - Cell Line
MH  - Cell Proliferation/*drug effects
MH  - Chemokine CCL2/*antagonists & inhibitors/biosynthesis
MH  - DNA Fragmentation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fibroblasts/*drug effects/immunology/pathology
MH  - Flow Cytometry
MH  - Kidney/*drug effects/immunology/pathology
MH  - Mycophenolic Acid/*pharmacology
MH  - Rats
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Necrosis Factor-alpha/*physiology
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
PMC - PMC2936834
EDAT- 2010/07/24 06:00
MHDA- 2010/12/14 06:00
PMCR- 2011/08/01
CRDT- 2010/07/24 06:00
PHST- 2010/07/24 06:00 [entrez]
PHST- 2010/07/24 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2011/08/01 00:00 [pmc-release]
AID - BPH837 [pii]
AID - 10.1111/j.1476-5381.2010.00837.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2010 Aug;160(7):1611-20. doi: 10.1111/j.1476-5381.2010.00837.x.