| In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor-alpha. | |
| | |
MedLine Citation:
|
PMID: 20649565 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Hong-Wei Chang; Vin-Cent Wu; Kwan-Dun Wu; Hong-Yu Huang; Bor-Shen Hsieh; Yung-Ming Chen |
Related Documents
:
|
11321045 - Role of apoptosis of renal tubular cells in acute renal failure: therapeutic implications. 22254105 - Perspectives on immunoglobulins in colostrum and milk. 7648225 - T-cell regulation of renal immune responses. 2968295 - The role of oxygen radicals in immune complex injury. 11673515 - Caspase 8 activity in membrane blebs after anti-fas ligation. 21605075 - Biomarkers for hepatocellular apoptosis in the management of liver diseases. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: British journal of pharmacology Volume: 160 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2010 Aug |
Date Detail:
|
Created Date: 2010-07-23 Completed Date: 2010-11-30 Revised Date: 2011-08-03 |
Medline Journal Info:
|
Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
|
Languages: eng Pagination: 1611-20 Citation Subset: IM |
Affiliation:
|
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Anti-Inflammatory Agents, Non-Steroidal / pharmacology* Apoptosis / drug effects Blotting, Western Caspase 3 / metabolism Cell Culture Techniques Cell Line Cell Proliferation / drug effects* Chemokine CCL2 / antagonists & inhibitors*, biosynthesis DNA Fragmentation / drug effects Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay Fibroblasts / drug effects*, immunology, pathology Flow Cytometry Kidney / drug effects*, immunology, pathology Mycophenolic Acid / pharmacology* Rats Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha / physiology* p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors |
| Chemical | |
Reg. No./Substance:
|
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Ccl2 protein, rat; 0/Chemokine CCL2; 0/Tumor Necrosis Factor-alpha; 24280-93-1/Mycophenolic Acid; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: IL-1beta induces expression of matrix metalloproteinase-9 and cell migration via a c-Src-dependent, ...
Next Document: Early growth response-1 induction by fibroblast growth factor-1 via increase of mitogen-activated pr...