Keratin-dependent, epithelial resistance to tumor necrosis factor- induced apoptosis

Carlos Caulin, Carl F. Ware, Thomas M. Magin, Robert G. Oshima

Research output: Contribution to journalArticlepeer-review

227 Scopus citations

Abstract

Tumor necrosis factor (TNF) is a cytokine produced by macrophages and T lymphocytes that acts through two distinct receptors, TNFR1 (60 kD, CD120a) and TNFR2 (80 kD, CD120b), to affect cellular proliferation, differentiation, survival, and cell death. In addition to its proinflammatory actions in mucosal tissue, TNF is important for liver regeneration. Keratin 8 (K8) and keratin 18 (K18) form intermediate filaments characteristic of liver and other single cell layered, internal epithelia and their derivative cancers. K8-deficient (K8-) mice, which escape embryonic lethality, develop inflammatory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatectomy poorly. We show that normal and malignant epithelial cells deficient in K8 and K18 are ~100 times more sensitive to TNF-induced death. K8 and K18 both bind the cytoplasmic domain of TNFR2 and moderate TNF- induced, Jun NH2-terminal kinase (JNK) intracellular signaling and NFκB activation. Furthermore, K8- and K18- mice are much more sensitive to TNF dependent, apoptotic liver damage induced by the injection of concanavalin A. This moderation of the effects of TNF may be the fundamental function of K8 and K18 common to liver regeneration, inflammatory bowel disease, hepatotoxin sensitivity, and the diagnostic, persistent expression of these keratins in many carcinomas.

Original languageEnglish (US)
Pages (from-to)17-22
Number of pages6
JournalJournal of Cell Biology
Volume149
Issue number1
DOIs
StatePublished - Apr 3 2000
Externally publishedYes

Keywords

  • Cytoskeleton
  • Intermediate filament inflammatory bowel disease
  • Tumor necrosis factor receptor 2

ASJC Scopus subject areas

  • Cell Biology

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