p38 MAPK mediates the regulation of α1(I) procollagen mRNA levels by TNF‐α and TGF‐β in a cell line of rat hepatic stellate cells¹

Abstract

The role of members of the mitogen-activated protein kinase (MAPK) family on tumor necrosis factor K K (TNF-K K)-mediated down-regulation of col1a1 gene was studied. TNF-K K increased extracellular-regulated kinase and Jun-N-terminal kinase phosphorylation, but these e¡ects were not related to its inhibitory e¡ect on K K1(I) procollagen (col1a1) mRNA levels. Phosphorylation of p38 MAPK was decreased in response to TNF-K K, and the speci¢c p38 MAPK inhibitor SB203580 mimicked the e¡ect of TNF-K K on col1a1 mRNA levels. Transforming growth factor L L (TGF-L L) increased p38 MAPK phosphorylation and SB203580 prevented the induction of col1a1 mRNA levels by TGF-L L. These results suggest that p38 MAPK plays an important role in regulating the expression of col1a1 in hepatic stellate cells in response to cytokines. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosisin vivo

“…This is consistent with the findings that inhibition of the p38 MAPK activity reduced type I collagen mRNA levels in primary rodent HSC. 46,47 Our findings demonstrate the presence of AB within HSC in vivo in three different models of fibrosis, confirming that phagocytic activity is indeed a physiologically relevant characteristic of these cells. The phagosomes indeed represent AB, because they are discrete particles surrounded by a double membrane.…”

Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling

“…It is also known that the NFB and MAPK pathways, including p38 and JNK, participate in HSC activation [45,46,47]. Therefore, we treatment of rats, and ongoing production of proinflammatory cytokines regulated by NFB is believed to play a major role in CCl 4 -induced liver fibrosis [48,49,50].…”

The p65 Subunit of NF-κB Inhibits COL1A1 Gene Transcription in Human Dermal and Scleroderma Fibroblasts through Its Recruitment on Promoter by Protein Interaction with Transcriptional Activators (c-Krox, Sp1, and Sp3)

“…COL1A1 (15,25) and COL1A2 (41,42), in fibroblasts or in other related cell types (24,43), via NF-B or other transcription factors (44 -46). For example, in rat hepatic stellate cells, a TNF-␣-inhibitory responsive element (T␣RE) between Ϫ378 and Ϫ345 bp has been characterized in Col1a1; it binds a complex including p20C/EBP␤, p35C/EBP␤, and C/EBP␦, following p38 mediation, and surprisingly, this DNA-binding element colocalizes with the TGF-␤-responsive element (43)(44)(45). Another mechanism of down-regulation of collagen synthesis by TNF-␣, associated with p65, has been shown to be necessary for the inhibition of TGF-␤-induced phosphorylation, nuclear translocation, and DNA binding of Smad signaling complexes.…”