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ENDOTOXIN INDUCIBLE TRANSCRIPTION IS REPRESSED IN ENDOTOXIN TOLERANT CELLS

ABSTRACT Stimulation of the human promonocytic cell line, THP‐1, with endotoxin results in a rapid and transient increase in interleukin 1&bgr; expression. Endotoxin pretreatment of THP‐1 cells results in tolerance, characterized by decreased levels of endotoxin‐induced interleukin 1&bgr; expression due to decreased transcription of the interleukin 1&bgr; gene. We hypothesized that tolerant cells could not activate transcription factors necessary to express the interleukin 1&bgr; gene. This hypothesis was tested in tolerant THP‐1 cells by using stable and transiently transfected reporter genes containing the interleukin 1&bgr; promoter. We found decreased endotoxin‐induced transcription of all reporter genes tested; however, individual transcription factors, such as NF&kgr;B, retain normal, CD14‐dependent, nuclear translocation and DNA binding. Tolerance is specific for endotoxin, because phorbol ester is still able to activate transcription of the endogenous interleukin 1&bgr; gene and transfected reporter genes. A constitutively active reporter gene that is not inducible by endotoxin is unaffected. We further show that nuclear extracts of tolerant cells show transcription inhibitor activity that is specific for promoter sequences of the interleukin 1&bgr; gene. These results support a mechanism of endotoxin tolerance that is independent of transcription factor DNA binding and appears to be associated with the inability of DNA‐bound transcription factors to activate transcription, perhaps through the activity of a repressor.