TGF-b-Induced matrix proteins inhibit p42/44 MAPK and JNK activation and suppress TNF-Mediated IkBa degradation and NF-kB nuclear translocation in L929 fibroblasts

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Abstract

The role of transforming growth factor b1 (TGF-b1)-induced extracellular matrix proteins in the modulation of cellular response to the cytotoxic effect of tumor necrosis factor (TNF) or Fas ligand was investigated. Murine L929 fibroblasts were prestimulated with or without TGF-b1 for 1-24 h and the resulting extracellular protein matrices were prepared. Unstimulated control L929 cells were then cultured on these matrices. Compared to control matrix-stimulated L929 cells, the TGF-b1 matrix-stimulated cells resisted TNF killing in the presence of actinomycin D (ActD), but became more susceptible to killing by anti-Fas antibodies/ActD. The induced TNF resistance is independent of the NF-kB antiapoptotic effect. For example, exposure of TGF-b1 matrix-stimulated L929 cells to TNF failed to result in IkBa degradation and NF-kB nuclear translocation or activation. Also, control matrix stimulated the activation of p42/44 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK in L929 cells, whereas TGF-b1 matrix suppressed the activation. Nonetheless, in response to TNF, JNK activation was restored in the TGF-b1 matrix-stimulated cells. By metabolic labeling, ammonium sulfate precipitation and N-terminal amino acid microsequencing, TGF-b1 was shown to induce a novel matrix protein of 46 kDa (p46) from L929 cells. Adsorption of p46 by peptide antibodies against its N-terminus removed the TGF-b1 matrix protein-mediated protection against TNF/ActD cytotoxicity and its enhancement of anti-Fas/ActD) killing, indicating that p46 is responsible for these effects. Immunostaining of L929 cells revealed that the antibodies were bound to a membrane protein of 100 kDa (p100). Thus, the matrix p46 is likely derived from the released membrane p100. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)194-200
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume267
Issue number1
DOIs
Publication statusPublished - 2000 Jan 7

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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