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 induced expression of endothelial cell adhesion molecules. The nuclear transcription factor kappa B (NF-kappa B) plays a critical role in the cytokine-induced expression of these genes in cultured endothelium. We examined 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 rapidly increased within lung and heart tissues of rats administered endotoxin, 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 promoter. NF-kappa B activation was maximal within 30 min and persisted for at least 3 hr after endotoxin treatment. NF-kappa B activation preceded 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 leukocytes and the development of pulmonary inflammation. NF-kappa B activation is therefore an early event in the initiation of acute inflammation in vivo. This molecular pathway may be of consequence in the pathogenesis of acute inflammatory disease.
Manning
A M
AM
Cell Biology and Inflammation Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
Bell
F P
FP
Rosenbloom
C L
CL
Chosay
J G
JG
Simmons
C A
CA
Northrup
J L
JL
Shebuski
R J
RJ
Dunn
C J
CJ
Anderson
D C
DC
D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D004731:Endotoxins / Q000494:pharmacology; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology; D007150:Immunohistochemistry; D007962:Leukocytes / Q000502:physiology*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D015345:Oligonucleotide Probes / Q000235:genetics; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015815:Cell Adhesion Molecules; D004731:Endotoxins; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D019007:P-Selectin; D009195:Peroxidase