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Signaling Cascades Leading to NF-
B Activation and IL-8 Expression in Human Intestinal Epithelial Cells1
*
Departments of Medicine, Microbiology, and Immunology and
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599
Cytokine signaling involves the participation of many adaptor
proteins, including the docking protein TNF receptor-associated
factor-2 (TRAF-2), which is believed to transmit the TNF-
signal
through both the I
B/NF-B and c-Jun N-terminal kinase
(JNK)/stress-related protein kinase (SAPK) pathways. The physiological
role of TRAF proteins in cytokine signaling in intestinal epithelial
cells (IEC) is unknown. We characterized the effect of a
dominant-negative TRAF-2 delivered by an adenoviral vector
(Ad5dnTRAF-2) on the cytokine signaling cascade in several IEC and also
investigated whether inhibiting the TRAF-2-transmitting signal blocked
TNF--induced NF-B and IL-8 gene expression. A high efficacy and
level of Ad5dnTRAF-2 gene transfer were obtained in IEC using a
multiplicity of infection of 50. Ad5dnTRAF-2 expression prevented
TNF--induced, but not IL-1ß-induced, IB degradation and
NF-B activation in NIH-3T3 and IEC-6 cells. TNF--induced JNK
activation was also inhibited in Ad5dnTRAF-2-infected HT-29 cells.
Induction of IL-8 gene expression by TNF- was partially inhibited in
Ad5dnTRAF-2-transfected HT-29, but not in control Ad5LacZ-infected,
cells. Surprisingly, IL-1ß-mediated IL-8 gene expression was also
inhibited in HT-29 cells as measured by Northern blot and ELISA. We
concluded that TRAF-2 is partially involved in TNF--mediated
signaling through IB/NF-B in IEC. In addition, our data suggest
that TRAF-2 is involved in IL-1ß signaling in HT-29 cells.
Manipulation of cytokine signaling pathways represents a new approach
for inhibiting proinflammatory gene expression in
IEC.
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