The CD40-CD40L Pathway Contributes to the Proinflammatory Function of Intestinal Epithelial Cells in Inflammatory Bowel Disease

• Published in: The American journal of pathology Vol. 176; no. 4; pp. 1816 - 1827
• Main Authors: Borcherding, Frauke, Nitschke, Martin, Hundorfean, Gheorghe, Rupp, Jan, von Smolinski, Dorthe, Bieber, Katja, van Kooten, Cees, Lehnert, Hendrik, Fellermann, Klaus, Büning, Jürgen
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2010; ASIP; American Society for Investigative Pathology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Biopsy; CD40 Antigens - biosynthesis; CD40 Ligand - biosynthesis; Epithelial Cells - metabolism; Female; Fibroblasts - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation; Humans; Inflammatory Bowel Diseases - metabolism; Interferon-gamma - metabolism; Interleukin-8 - metabolism; Intestines - metabolism; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Middle Aged; Other diseases. Semiology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Remission Induction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Crohn disease; Anatomic pathology; Digestive system; CD40 ligand; Gut; Digestive diseases; Intestinal disease; Epithelial cell; Inflammation; Inflammatory disease; Ulcerative colitis
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2010.090461

In inflammatory bowel diseases (IBD), intestinal epithelial cells (IECs) are involved in the outbalanced immune responses toward luminal antigens. However, the signals responsible for this proinflammatory capacity of IECs in IBD remain unclear. The CD40/CD40L interaction activates various pathways in immune and nonimmune cells related to inflammation and was shown to be critical for the development of IBD. Here we demonstrate CD40 expression within IECs during active IBD. Endoscopically obtained biopsies taken from Crohn’s disease ( n = 112) and ulcerative colitis patients ( n = 67) consistently showed immunofluorescence staining for CD40 in IECs of inflamed ileal or colonic mucosa. In noninvolved mucosa during active disease, tissue obtained during Crohn’s disease or ulcerative colitis in remission and biopsies from healthy controls ( n = 38) IECs almost entirely lacked CD40 staining. Flow cytometry and RT-PCR analysis using different intestinal epithelial cell lines (HT29, SW480, and T84) showed IFN-γ to effectively induce CD40 in IECs. Cells were virtually unresponsive to LPS or whole E. coli regarding CD40 expression. In addition, a moderate induction of CD40 was found in response to TNF-α, which exerted synergistical effects with IFN-γ. CD40 ligation by CD40L-transfected murine fibroblasts or soluble CD40L increased the secretion of IL-8 in IFN-γ pretreated HT29 cells. Our findings provide evidence for the epithelial expression and modulation of CD40 in IBD-affected mucosa and indicate its involvement in the proinflammatory function of IECs.