These results (1) confirm the role of soluble TNFα in hepatic Cyp3a regulation during infectious colitis deduced from studies in TNFα receptor-1 knockout mice; (2) indicate the potential for soluble TNFα -specific antagonists to cause disease-dependent drug–drug interactions; and (3) suggest a novel mechanism by which an anti-inflammatory therapeutic protein can produce an opposite effect to that of the disease by selectively neutralizing one of multiple signals regulating drug-metabolizing enzyme expression. This evidence concerns the gene CYP3A4 and infectious colitis.