TISSUE REMODELING DURING TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS IN LLC-PK1 RENAL EPITHELIAL-CELLS

The cytokine tumor necrosis factor-alpha (TNF) increases the frequency of apoptosis in confluent renal epithelial LLC-PK1 cells, an effect t hat can be blocked by an anti-TNFR1 monoclonal antibody. However, ther e were no visible ''holes'' in the cell sheet as a result of TNF-induc ed apoptosis. Instead a striking tissue remodeling occurred in respons e to the TNF-induced apoptosis. Apoptotic cells became surrounded and engulfed by repositioned neighboring cells distributed in a distinct ' 'rosette'' pattern. The cadherin-catenin cell-cell adhesion molecules, the tight junction-associated protein ZO-1, and actin accumulated at the sites of contact between apoptotic and neighboring cells. Pretreat ment with cytochalasin B prevented the accumulation of cadherins-caten ins and ZO-1 at the sites of apoptosis and resulted in microscopic hol es in the TNF-treated cell sheet. Our results indicate that a renal ep ithelium can accommodate an increased frequency of apoptosis and still maintain its integrity by mechanisms of tissue remodeling involving t he cadherin-catenin adhesion molecules, tight junctional proteins, and actin filaments.