Tumor Necrosis Factor- Induces Transforming Growth Factor- 1 Expression in Lung Fibroblasts Through the Extracellular Signal–Regulated Kinase Pathway
نویسندگان
چکیده
Increased expression of transforming growth factor (TGF)1 and tumor necrosis factor (TNF)are thought to play important roles in the development of pulmonary fibrosis. We recently reported that TNFupregulates TGF1 expression in primary mouse lung fibroblasts (MLFs), a key cell population in fibrogenesis. In the present study, we have investigated signal transduction pathways involved in TNFupregulation of TGF1 in both primary MLFs and the Swiss 3T3 fibroblast cell line. Treatment of fibroblasts with TNFresulted in a significant increase in TGF1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNFactivated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNFinduction of TGF1 mRNA and protein. mRNA stability experiments showed that TNFincreased the half-life of TGF1 mRNA to more than 24 h compared with 15 h in unstimulated cells. Expression of constitutively active MEK1 that selectively phosphorylates ERK was sufficient for TGF1 mRNA stabilization in Swiss 3T3 fibroblasts. These results indicate that TNFactivates the ERK-specific mitogenactivated protein kinase pathway leading to increased TGF1 production in fibroblasts, primarily via a post-transcriptional mechanism that involves stabilization of the TGF1 transcript.
منابع مشابه
Basic Fibroblast Growth Factor Antagonizes Transforming Growth Factor- 1–Induced Smooth Muscle Gene Expression Through Extracellular Signal–Regulated Kinase 1/2 Signaling Pathway Activation
متن کامل
Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes
INTRODUCTION The objective of this study was to model the effects of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF), both present in rheumatoid arthritis (RA) synovia, on the behavior of fibroblast-like synoviocytes (FLS) in response to pro-inflammatory cytokine (interleukin (IL)1beta, tumor necrosis factor-alpha (TNFalpha)) challenge. METHODS Gene and pr...
متن کاملBcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis.
Evidence shows that Bcl-2 family members play a direct role in the development of some human malignancies. However, the mechanism by which Bcl-2 may influence tumor cell invasion and metastasis remains unclear. Ectopic overexpression of Bcl-2 in the human squamous carcinoma cell line HSC-3 enhanced tumorigenicity and experimental pulmonary metastasis. Interestingly, Bcl-2-expressing cells showe...
متن کاملReactive oxygen species mediate TNF-α-induced inflammatory response in bone marrow mesenchymal cells
Objective(s): It is generally believed that the inflammatory response in bone marrow mesenchymal stem cells (BMSCs) transplantation leads to poor survival and unsatisfactory effects, and is mainly mediated by cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α). In this study, we explored the mechanisms underlying the TNF-α-induced inflammatory ...
متن کاملSmad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-beta-induced expression of connective tissue growth factor in human fibroblasts.
Connective tissue growth factor (CTGF) is secreted by fibroblasts stimulated with transforming growth factor-beta (TGF-beta). CTGF is a potent enhancer of fibroblast proliferation, chemotaxis, and extracellular matrix deposition, and it is thought to mediate some of the fibrogenic effects of TGF-beta. Here, we have elucidated signaling pathways involved in regulating the TGF-beta-induced produc...
متن کامل