Immunomodulatory Drug CC-4047 is a Cell-type and Stimulus-Selective Transcriptional Inhibitor of Cyclooxygenase 2

• Published in: Journal of Clinical Immunology Vol. 27; no. 2; pp. 210 - 220
• Main Authors: Ferguson, Gregory D., Jensen-Pergakes, Kristen, Wilkey, Candice, Jhaveri, Urvi, Richard, Normand, Verhelle, Dominique, De Parseval, Laure Moutouh, Corral, Laura G., Xie, Weilin, Morris, Christopher L., Brady, Helen, Chan, Kyle
• Format: Journal Article
• Language: English
• Published: Netherlands Springer Nature B.V 01.03.2007
• Subjects: Anemia, Sickle Cell - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Blotting, Western; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 Inhibitors - pharmacology; Drug Synergism; Gene Expression - drug effects; Humans; Immunologic Factors - pharmacology; Immunoprecipitation; Lipopolysaccharides - pharmacology; Membrane Proteins - drug effects; Monocytes - drug effects; Monocytes - metabolism; Nitrobenzenes - pharmacology; Prostaglandins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides - pharmacology; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Transcription, Genetic - drug effects
• ISSN: 0271-9142; 1573-2592; 1365-2567
• DOI: 10.1007/s10875-007-9070-6

COX2 (prostaglandin G/H synthase, PTGS2) is a well-validated target in the fields of both oncology and inflammation. Despite their significant toxicity profile, non-steroidal anti-inflammatory drugs (NSAIDs) have become standard of care in the treatment of many COX2-mediated inflammatory conditions. In this report, we show that one IMiDs((R)) immunomodulatory drug, CC-4047, can reduce the levels of COX2 and the production of prostaglandins (PG) in human LPS-stimulated monocytes. The inhibition of COX2 by CC-4047 occurs at the level of gene transcription, by reducing the LPS-stimulated transcriptional activity at the COX2 gene. Because it is a transcriptional rather than an enzymatic inhibitor of COX2, CC-4047 inhibition of PG production is not susceptible to competition by exogenous arachadonic acid (AA). The distinct mechanisms of action allow CC-4047 and a COX2-selective NSAID to work additively to block PG secretion from monocytes. CC-4047 does not, however, block COX2 induction in or prostacyclin secretion from IL-1beta stimulated human umbilical vein endothelial cells (HUVEC) cells, nor does it inhibit COX1 in either monocytes or HUVEC cells. CC-4047 also inhibits COX2 and PG production in monocytes derived from patients with sickle cell disease (SCD). Taken together, the data in this manuscript suggest CC-4047 will provide important anti-inflammatory benefit to patients and will improve the safety of NSAIDs in the treatment of SCD or other inflammatory conditions.