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Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin
- Source :
- Biochemical Pharmacology. 81:134-143
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- The mTOR-inhibitor rapamycin is a potent drug used in many immunosuppressive and antiinflammatory therapeutic regimes. In renal transplantation despite its beneficial roles rapamycin in some cases can promote renal fibrosis in the kidney but the underlying mechanisms are unknown. In this study, we tested for possible modulatory effects of rapamycin on the cytokine-triggered matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase (TIMP)-1 protease-antiprotease system which is critically involved in renal inflammation and fibrosis. Treatment of rat mesangial cells (MC) with rapamycin dose-dependently reduced the interleukin 1β (IL-1β)-triggered increase in gelatinolytic levels as demonstrated by zymography. The reduction in the extracellular MMP-9 content by rapamycin coincided with an attenuation in cytokine-induced steady-state MMP-9 mRNA levels. Conversely, rapamycin caused a dose-dependent increase in cytokine-evoked TIMP-1 expression in a Smad binding element (SBE)-dependent manner. Surprisingly, the attenuation of MMP-9 mRNA levels by rapamycin is accompanied by a potentiation of IL-1β-induced MMP-9 promoter activity in which the stimulatory effects by rapamycin are mainly attributed to a proximal AP-1 binding site. Furthermore, the rapamycin-dependent potentiation of MMP-9 expression is accompanied by an amplification of cytokine-triggered activities of nuclear factor κB (NF-κB) and activator protein 1 (AP-1) transcription factors. Importantly, rapamycin-triggered increase in MMP-9 promoter activity is fully impaired when we used a MMP-9 reporter construct which is under the additional control of the 3' untranslated region (3'-UTR) of MMP-9. Collectively, these data imply that rapamycin inhibits the cytokine-induced MMP-9 mainly through posttranscriptional events and thereby exerts profibrotic activities.
- Subjects :
- Nucleocytoplasmic Transport Proteins
Proto-Oncogene Proteins c-jun
medicine.medical_treatment
Matrix metalloproteinase
Biology
Biochemistry
Fibrosis
medicine
Renal fibrosis
Animals
RNA, Messenger
3' Untranslated Regions
Transcription factor
Cells, Cultured
Sirolimus
Pharmacology
Kidney
Tissue Inhibitor of Metalloproteinase-1
TOR Serine-Threonine Kinases
Tissue inhibitor of metalloproteinase
medicine.disease
Molecular biology
Neoplasm Proteins
Rats
Transplantation
medicine.anatomical_structure
Cytokine
Gene Expression Regulation
Matrix Metalloproteinase 9
Mesangial Cells
Dactinomycin
Cancer research
Cytokines
Immunosuppressive Agents
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 81
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....80093b491282e1961fa6b4655fa7c439