A new transcription factor that regulates TNF-α gene expression, LITAF, is increased in intestinal tissues from patients with CD and UC

Abstract

BACKGROUND: The proinflammatory cytokine tumor necrosis factor-α (TNF-α) plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Recently, a new transcription factor termed LITAF (lipopolysaccharide-induced TNF-α factor) was shown to mediate TNF-α expression in human macrophages by direct binding to specific sequences in the promoter region of the TNF-α gene. METHODS: In this report, we identified LITAF in resected ileal and colonic tissues from patients with CD and UC by immunohistochemistry, real-time polymerase chain reaction, and Western blot analysis. LITAF expression in inflamed and noninflamed areas of the tissues was compared. RESULTS: This is the first demonstration of LITAF, a newly discovered transcription factor that regulates TNF-α gene transcription in ileal and colonic tissues from patients with either CD or UC. LITAF immunostaining was localized to lamina propria macrophages and was markedly increased relative to tissues from controls without inflammatory bowel disease. In patients with CD, a 5-fold increase in LITAF mRNA was measurable in noninflamed colonic tissues compared with controls without inflammatory bowel disease. LITAF mRNA in tissues from inflamed areas of the colon was increased by an additional 60% compared with noninflamed tissues. In patients with UC, LITAF mRNA levels in colonic tissues resected from noninflamed areas were elevated 15-fold above nondisease controls, but they were not different in tissues resected from inflamed areas. Western blot analysis showed that in patients with CD, there was a marked increase in LITAF protein in inflamed areas compared with noninflamed areas. LITAF protein levels were not different between noninflamed and inflamed tissues obtained from patients with UC. TNF-α mRNA and protein levels paralleled LITAF. Similarly, in inflamed ileal tissues from patients with CD, LITAF is also localized to lamina propria macrophages. LITAF mRNA and LITAF protein were significantly increased in inflamed ileal tissues compared with noninflamed areas. CONCLUSIONS: LITAF is readily detectable in ileal and colonic tissues from patients with either CD or UC, is significantly elevated above controls, and is localized to macrophages, a major source of TNF-α. These data provide strong evidence of a role for LITAF in the pathophysiological regulation of the TNF-α gene and underscore the potential value of anti-LITAF strategies in the clinical management of these diseases. Copyright © 2006 by Lippincott Williams & Wilkins.