Scientific Abstract
Proposal No. IBD-0116R
Principal Investigator: Christian Jobin, Ph.D.
Applicant Organization: University of North Carolina at Chapel Hill (U.S.A.)
Project Title: Modulation of innate signal transduction and experimental colitis by natural plant extracts
Period of Award: July 1, 2004 - December 31, 2005
Gram-negative bacteria and their product lipopolysaccharide (LPS) utilize the toll-like receptor (TLR) pathway to signal to various down-stream effector systems, including the NF-κB transcriptional system. NF-κB regulates the transcription of numerous proinflammatory and immune related genes and is a major effector pathway induced by the innate immune pathway. Dysregulated innate immune responses to the intestinal endogenous microflora are associated with intestinal inflammatory disorders. Interestingly, an emerging hypothesis proposes that human inflammatory bowel diseases (IBD) are caused by a loss of tolerance toward the host’s own endogenous microflora. However, rather limited therapeutic approaches are currently available to modulate innate signaling and intestinal inflammation. Nontraditional medicine such as “herbal medicine” is becoming an increasingly attractive approach for the treatment/ prevention of various inflammatory disorders, especially in patients unresponsive to, or unwilling to take standard therapeutic regimen. Natural product chemists have isolated a large number of compounds from the plant kingdom that may block inflammation and/or cancer. These products have captured the imagination of the public who are interested in a "natural" approach to disease prevention. However, the impact of natural plant extracts on bacterial-induced innate immunity is currently unknown.
Our preliminary data show that the natural plant extracts luteolin and tanshinone inhibit LPS-induced NF-kB activity in vitro in intestinal epithelial cells (IEC) and in bone marrow-derived dendritic cells (BMDC). We propose to examine the effect of certain nutraceuticals on innate signaling and inflammation. In this study, we hypothesize that selective natural plant extracts downregulate innate immune responses and help maintain intestinal homeostasis. We will test this hypothesis with two SPECIFIC AIMS: 1) Evaluate the effect of natural plant extracts on acute and chronic experimental colitis; 2) Determine the mechanism(s) by which natural plant extracts modulate LPS-induced NF-κB activation. Understanding the impact of natural plant extracts on innate signaling pathway will lead to new therapeutical avenues for the treatment of IBD. Modulation of innate signal transduction by natural plant extracts could be a major step toward the development of potent and safe therapies for intestinal inflammation.