TY - JOUR
T1 - Keratin-dependent, epithelial resistance to tumor necrosis factor- induced apoptosis
AU - Caulin, Carlos
AU - Ware, Carl F.
AU - Magin, Thomas M.
AU - Oshima, Robert G.
PY - 2000/4/3
Y1 - 2000/4/3
N2 - 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.
AB - 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.
KW - Cytoskeleton
KW - Intermediate filament inflammatory bowel disease
KW - Tumor necrosis factor receptor 2
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U2 - 10.1083/jcb.149.1.17
DO - 10.1083/jcb.149.1.17
M3 - Article
C2 - 10747083
AN - SCOPUS:0034599872
SN - 0021-9525
VL - 149
SP - 17
EP - 22
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -