NF-KAPPA-B IS ACTIVATED DURING ACUTE-INFLAMMATION IN-VIVO IN ASSOCIATION WITH ELEVATED ENDOTHELIAL-CELL ADHESION MOLECULE GENE-EXPRESSION AND LEUKOCYTE RECRUITMENT

Leukocytes accumulate at sites of inflammation in response to the indu ced expression of endothelial cell adhesion molecules. The nuclear tra nscription factor kappa B (NF-kappa B) plays a critical role in the cy tokine-induced expression of these genes in cultured endothelium. We e xamined the relationship between NF-kappa B activation and endothelial cell adhesion molecule gene expression in vivo during the initiation of acute inflammation. Nuclear NF-kappa B DNA-binding activity was rap idly increased within lung and heart tissues of rats administered endo toxin, consistent with the translocation of NF-kappa B complexes from the cytoplasm to the nucleus. This NF-kappa B was composed of p50 and p65 subunits and could bind NF-kappa B elements in the E-selectin prom oter. NF-kappa B activation was maximal within 30 min and persisted fo r at least 3 hr after endotoxin treatment. NF-kappa B activation prece ded the transcriptional activation of the P-selectin, E-selectin, VCAM -1, and ICAM-1 genes. In the lung, increased expression of P-selectin and ICAM-1 protein was detected immunohistochemically. These molecular events were temporally associated with the sequestration of leukocyte s and the development of pulmonary inflammation. NF-kappa B activation is therefore an early event in the initiation of acute inflammation i n vivo. This molecular pathway may be of consequence in the pathogenes is of acute inflammatory disease. (C) 1995 Wiley-Liss, Inc.