Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) mediates a wide variety of disease states including septic shock, acute and chronic inflammation, and cachexia. Recently, a multivalent guanylhydrazone (CNI-1493) developed as an inhibitor of macrophage activation was shown to suppress TNF production and protect against tissue inflammation and endotoxin lethality [Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G. A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B., Manogue, K. R., Tortolani, A. J., Cerami, A. & Tracey, K. J. (1995) Mol. Med. 1, 254-266, and Bianchi, M., Bloom, O., Raabe, T., Cohen, P. S., Chesney, J., Sherry, B., Schmidtmayerova, H., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A. & Tracey, J. (1996) J. Exp. Med., in press]. We have now elucidated the mechanism by which CNI-1493 inhibits macrophage TNF synthesis and show here that it acts through suppression of TNF translation efficiency. CNI-1493 blocked neither the lipopolysaccharide (LPS)-induced increases in the expression of TNF mRNA nor the translocation of nuclear factor NF-kappa B to the nucleus in macrophages activated by 15 min of LPS stimulation, indicating that CNI-1493 does not interfere with early NF-kappa B-mediated transcriptional regulation of TNF. However, synthesis of the 26-kDa membrane form of TNF was effectively blocked by CNI-1493. Further evidence for the translational suppression of TNF is given by experiments using chloram-phenicol acetyltransferase (CAT) constructs containing elements of the TNF gene that are involved in TNF translational regulation. Both the 5' and 3' untranslated regions of the TNF gene were required to elicit maximal translational suppression by CNI-1493. Identification of the molecular target through which CNI-1493 inhibits TNF translation should provide insight into the regulation of macrophage activation and mechanisms of inflammation.
 ...
PMID:CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. 863 99

Transendothelial leukocyte trafficking during inflammation requires the expression of adhesion molecules such as human intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is constitutively expressed on the surface of endothelial cells and its levels increase in response to a variety of inflammatory mediators, including cytokines. Monocyte/macrophage cells play a crucial role in this context because, upon stimulation, they release proinflammatory cytokines which are responsible for the upregulation of adhesion molecules in endothelial cells. In the present study we investigated whether the modulation of macrophage activation and cytokine release is able to modulate ICAM-1 expression in endothelial cells. Dexamethasone was selectively delivered to macrophages by means of a red blood cell-mediated delivery system. Subsequent stimulation of macrophages by lipopolysaccharide (LPS) was found to inhibit NF-kB activation and tumor necrosis factor-alpha (TNF-alpha) release [R. Crinelli, A. Antonelli, M. Bianchi, L. Gentilini, S. Scaramucci, and M. Magnani (2000) Blood Cells Mol. Dis. 26, 211-222]. Incubation with conditioned medium derived from LPS-stimulated macrophages receiving dexamethasone resulted in a 45% inhibition of ICAM-1 mRNA expression in ECV304 cells. In the same experimental system this reduced ICAM-1 expression was paralleled by a reduced NF-kB DNA binding activity and a twofold higher level of IkB(alpha) in the cytosol of endothelial cells. Activation of ICAM-1 expression in ECV304 cells by macrophage-conditioned medium is not due to IFN-gamma stimulation since STAT-1 DNA binding remained unchanged. Furthermore, treatment of the macrophage-conditioned medium with a TNF-alpha-inactivating antibody resulted in the complete abrogation of induced ICAM-1 expression. These results suggest that TNF-alpha is the main cytokine released by LPS-stimulated macrophages able to promote ICAM-1 gene expression in endothelial cells. Modulation of the NF-kB activation pathway in macrophages by targeted delivery of dexamethasone could potentially be used as a therapeutic strategy with which to inhibit the expression of ICAM-1 in endothelial cells.
 ...
PMID:Modulation of ICAM-1 expression in ECV304 cells by macrophage-released cytokines. 1183 64