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

Tumor necrosis factor (TNF) is a cytokine produced by macrophages and T lym phocytes that acts through two distinct receptors, TNFR1 (60 kD, CD120a) an d TNFR2 (80 kD, CD120b), to affect cellular proliferation, differentiation, survival, and cell death. In addition to its proinflammatory actions in mu cosal tissue, TNF is important for liver regeneration. Keratin 8 (K8) and k eratin 18 (K18) form intermediate filaments characteristic of liver and oth er single cell layered, internal epithelia and their derivative cancers. K8 -deficient (K8(-)) mice, which escape embryonic lethality, develop inflamma tory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatec tomy poorly. We show that normal and malignant epithelial cells deficient i n K8 and K18 are similar to 100 times more sensitive to TNF-induced death. KS and K18 both bind the cytoplasmic domain of TNFR2 and moderate TNF-induc ed, Jun NH2-terminal kinase (JNK) intracellular signaling and NF kappa B ac tivation. 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 o f K8 and K18 common to liver regeneration, inflammatory bowel disease, hepa totoxin sensitivity, and the diagnostic, persistent expression of these ker atins in many carcinomas.