Fibronectin and cytokines increase JNK, ERK, AP-1 activity, and transin gene expression in rat hepatic stellate cells

Abstract

Cytokines, growth factors, and alterations in the extracellular matrix composition may play a role in maintaining hepatic stellate cells (HSC) in the activated state that is responsible for hepatic fibrogenesis. However, the signal transduction pathways that are stimulated by these factors in HSC remain to be fully elucidated. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) family, including c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), plays an important role in the cellular response to stress. The aims of this study were to investigate whether fibronectin (FN) or the inflammatory cytokines interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α) activate JNK, ERK, and AP-1 activity in HSC and induce the gene expression of the matrix metalloproteinase transin. Treatment of HSC with FN resulted in an up to 4.5-fold increase in ERK activity and a 2.1-fold increase in JNK activity. IL-1α and TNF-α produced up to a fourfold increase in JNK activity and a twofold increase in ERK activity. We then compared the effects of FN, IL-1α, and TNF-α on AP-1 activity and metalloproteinase mRNA induction. All three compounds increased AP-1 binding and promoter activity, and transin mRNA levels were increased 1.8-fold by FN, 2.2-fold by IL-1α, and 2.8-fold by TNF-α. Therefore, FN and inflammatory cytokines increase MAPK activity, stimulate AP-1 activity, and increase transin gene expression in HSC. Signal transduction pathways involving the MAPK family may play an important role in the regulation of matrix metalloproteinase expression by cytokines and FN in HSC.

The DNA Binding Protein BTEB Mediates Acetaldehyde-Induced, Jun N-Terminal Kinase-Dependent αI(I) Collagen Gene Expression in Rat Hepatic Stellate Cells

“…Additional studies were focused on signal transduction pathways to determine how the acetaldehyde signal was transduced to stimulate the activation of the ␣I(I) collagen gene promoter in HSC. It has been shown that fibronectin and inflammatory cytokines, such as TNF-␣ and IL-1␣, activated JNK and AP-1 in rat HSC (29). HNE, an aldehydic product of lipid peroxidation, was found to interact directly with JNK in human HSC (27).…”

“…While the ERK-stimulatory signal was mapped to the most proximal NF-1 and SP-1 binding domains of the 5Ј UPS of the gene, a distal GC box (Ϫ1484 to Ϫ1476) in the 5Ј UPS of the gene played a central role in receiving extracellular signals through the JNK pathway (8). A recent study also reported that fibronectin and inflammatory cytokines, such as interleukin 1␣ (IL-1␣) and tumor necrosis factor alpha (TNF-␣), activated JNK, ERK, and AP-1 in rat HSC (29). 4-Hydroxy-2,3-nonenal (HNE), an aldehydic product of lipid peroxidation, was found to interact directly with JNK in human HSC (27).…”

Cytokine Regulation of Periportal Fibrosis in Humans Infected with Schistosoma mansoni: IFN-γ Is Associated with Protection Against Fibrosis and TNF-α with Aggravation of Disease

“…This and experimental results discussed above suggest that TNF-␣ could act on fibrosis by balancing the protective effect of IFN-␥. TNF-␣ has pleiotropic effects on the immune response against schistosomes: it restores the ability of T cell-deficient mice to mount a granuloma around schistosome eggs (24); it increases ECMP production by Kupffer cells (36); it stimulates MP gene expression (40) and protects IL-12-vaccinated mice against the deleterious effects of the granuloma (23); TNF-␣ also increases the production of NO, whose hypotensive effects might benefit subjects with portal hypertension (41). Then, the primary role of TNF-␣ in schistosomiasis is a protective one.…”

Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis

“…We presently do not know the effect of increased fibronectin on RCS cells. Addition of fibronectin to hepatic stellate or lung carcinoma cells results in Erk activation (Poulos et al, 1997;Han et al, 2005) and thus FGF2-induced fibronectin may contribute to the maintenance of long-term Erk activity in RCS cells and thereby to FGF2-mediated growth arrest. Additional experiments are now ongoing to test this hypothesis.…”