Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate prevents In vivo expression of proinflammatory genes.
Background-The inability to inhibit multiple mediators of septic shock represents a major hurdle in the treatment of septic shock. In vivo inhibition of nuclear factor (NF)-kappaB activation, a transcription factor regulating expression of many proinflammatory genes, could provide a useful strategy for the treatment of septic shock. Methods and Results-In rats challenged with lipopolysaccharide (LPS) 8 mg/kg IV, we determined the time course of NF-kappaB activation and expression of multiple inflammatory signals: tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM)-1. We studied the effects of in vivo inhibition of NF-kappaB activation using pyrrolidine dithiocarbamate (PDTC) on the expression of these mediators. NF-kappaB activation preceded the induction of TNF-alpha, COX-2, CINC, and ICAM-1 mRNAs. PDTC prevented the LPS-induced NF-kappaB activation but did not inhibit activation of the transcription factors AP-1, Sp-1, and CREB. PDTC inhibited the LPS-induced expression of TNF-alpha, COX-2, CINC, and ICAM-1 mRNA and proteins and reduced the LPS-induced increases in plasma TNF-alpha, 6-keto-prostaglandin F(1alpha), and CINC concentrations. Inhibition of expression of these mediators prevented the increases in myeloperoxidase activity (a measure of neutrophil sequestration) in the heart, lungs, and liver. Conclusions-NF-kappaB activation correlates with LPS-induced expression of TNF-alpha, COX-2, CINC, and ICAM-1 genes in vivo. PDTC inhibits NF-kappaB activation and expression of these proinflammatory genes and their products. Thus, blocking NF-kappaB activation may be an effective strategy in the treatment of septic shock.
Liu
S F
SF
Department of Pharmacology, the University of Illinois College of Medicine, Chicago 60612.
Ye
X
X
Malik
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AB
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism; D051546:Cyclooxygenase 2; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases