The focus of research in our laboratory has centered on the role of the intestinal
and colonic epithelial cells in the inflammatory response at these sites. Intestinal
epithelial cells comprise a single layer of cells, which form the barrier between
the tissues of the body and the intestinal contents (including food material, bacteria,
viruses, toxins, etc.). As such, these cells can act as sentry cells to warn the body’s
immune system of an infection, wounding or the presence of a toxin. One major way
in which these cells send alarms is by secreting a variety of inflammatory cytokines
(or soluble factors) that can have many effects on nearby cells. These inflammatory
cytokines include tumor necrosis factor and interleukin-6 (IL-6), which are potent
pro-inflammatory cytokines, and several chemokines such as IL-8, monocyte chemoattractant
protein-1, and others, which induce inflammatory and immune cells from the blood to
migrate into the tissues.
Our studies have focused on mechanisms that regulate cytokine responses by the epithelial cells. In one study, we have examined the role of the extracellular matrix (ECM) and the cell surface integrins that bind to the ECM in regulating the capacity of intestinal epithelial cells to produce inflammatory cytokines. Experiments showed that one integrin in particular, the alpha3 beta1 integrin, may have a significant regulatory role in intestinal epithelial cells. Using cultured epithelial cell lines, we have found that cross-linking of this alpha3 beta1 integrin by using an antibody induces the cell to produce significantly lower levels of IL-6, IL-8 and MCP-1. Further experiments determined that activation of the alpha3 integrin resulted in a suppression of IL-1 induced intracellular signaling through TRAF6 and subsequently IkappaB/NF-KappaB and JNK/AP-1.
Our present studies are now determining the role of the Rho Kinase, ROCK, in regulating pro-inflammatory cytokine (IL-1 and TNF) signaling in intestinal epithelial cells. Inhibiting ROCK results in a suppression of IL-1 stimulated responses, such as cytokine secretion, and IL-1 intracellular signaling. We are also examining the role of inflammatory cytokines in regulating the expression of cell-cell interaction tight junction proteins like the claudins. These studies should allow a better understanding of the role of epithelial cells and inflammatory cytokines in the inflammatory response at the intestinal mucosa and wound healing.