The COX-2 Inhibitor NS-398 Causes T-Cell Developmental Disruptions Independent of COX-2 Enzyme Inhibition

• Published in: Cellular immunology Vol. 214; no. 2; pp. 184 - 193
• Main Authors: Xu, Hui, Izon, David J., Loftin, Charles, Spain, Lisa M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.12.2001
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - toxicity; cellular differentiation; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - toxicity; Dinoprostone - pharmacology; Dinoprostone - physiology; Immunologic Deficiency Syndromes - chemically induced; Indomethacin - analogs & derivatives; Indomethacin - pharmacology; Indomethacin - toxicity; Isoenzymes - antagonists & inhibitors; Isoenzymes - deficiency; Isoenzymes - genetics; Isoenzymes - physiology; lipid mediators; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Nitrobenzenes - pharmacology; Nitrobenzenes - toxicity; Organ Culture Techniques; Prostaglandin-Endoperoxide Synthases - deficiency; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - physiology; Receptors, Prostaglandin E - deficiency; Receptors, Prostaglandin E - genetics; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Sulfonamides - pharmacology; Sulfonamides - toxicity; T-Lymphocytes - pathology; Thiophenes - pharmacology; thymus; Thymus Gland - embryology; Thymus Gland - immunology; Thymus Gland - pathology; transgenic/knockout; transgenic/knockout; lipid mediators; thymus; cellular differentiation
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1006/cimm.2001.1891

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the function of cyclooxygenases, COX-1 and COX-2, which catalyze the first step in the synthesis of inflammatory mediators (PGE2). We sought to understand the roles of cyclooxygenases and NSAIDs in T-cell development. Our data show no significant defects in T-cell development in fetal thymic organ cultures of mice disrupted in both or either COX genes or in mice disrupted in either EP-1 or EP-2 receptor genes. On the other hand, NSAIDs reproducibly caused thymocyte developmental defects. However, the specific effects of the COX-2 inhibitors were not correlated with their potency for inhibition of COX-2 activity. We focused on the NS-398 COX-2 inhibitor and showed that its effects could not be reversed by exogenous PGE2. Furthermore, NS-398 was inhibitory even when its target, COX-2, was absent. These data show that the T-cell developmental effects of NS-398 are COX-2 and PGE2 independent.