Human Genome Screen to Identify the Genetic Basis of the Anti-inflammatory Effects of Boswellia in Microvascular Endothelial Cells

Human Genome Screen to Identify the Genetic Basis of the Anti-inflammatory Effects of Boswellia in Microvascular Endothelial Cells

Roy, Sashwati & Khanna, Savita & Shah, Hiral & Rink, Cameron & Phillips, Christina & Preuss, Harry & Subbaraju, Gottumukkala & Trimurtulu, Golakoti & Alluri, Kr & Bagchi, Mihir & Bagchi, Debasis & Sen, Chandan

(2005) DNA AND CELL BIOLOGY. 24. 244-55. 10.1089/dna.2005.24.244.

Abstract

Inflammatory disorders represent a substantial health problem. Medicinal plants belonging to the Burseraceae family, including Boswellia, are especially known for their anti-inflammatory properties. The gum resin of Boswellia serrata contains boswellic acids, which inhibit leukotriene biosynthesis. A series of chronic inflammatory diseases are perpetuated by leukotrienes. Although Boswellia extract has proven to be anti-inflammatory in clinical trials, the underlying mechanisms remain to be characterized. TNFa represents one of the most widely recognized mediators of inflammation. One mechanism by which TNFa causes inflammation is by potently inducing the expression of adhesion molecules such as VCAM-1. We sought to test the genetic basis of the anti-inflammatory effects of BE (standardized Boswellia extract, 5-Loxin) in a system of TNFa-induced gene expression in human microvascular endothelial cells. We conducted the first whole genome screen for TNFa- inducible genes in human microvascular cells (HMEC). Acutely, TNFa induced 522 genes and downregulated 141 genes in nine out of nine pairwise comparisons. Of the 522 genes induced by TNFa in HMEC, 113 genes were clearly sensitive to BE treatment. Such genes directly related to inflammation, cell adhesion, and proteolysis. The robust BE-sensitive candidate genes were then subjected to further processing for the identification of BE-sensitive signaling pathways. The use of resources such as GenMAPP, KEGG, and gene ontology led to the recognition of the primary BE-sensitive TNFa-inducible pathways. BE prevented the TNFa-induced expression of matrix metalloproteinases. BE also prevented the inducible expression of mediators of apoptosis. Most strikingly, however, TNFa-inducible expression of VCAM-1 and ICAM-1 were observed to be sensitive to BE. Real-time PCR studies showed that while TNFa potently induced VCAM-1 gene expression; BE completely prevented it. This result confirmed our microarray findings and built a compelling case for the anti-inflammatory property of BE. In an in vivo model of carrageenan-induced rat paw inflammation, we observed a significant anti-inflammatory property of BE consistent with our in vitro findings. These findings warrant further research aimed at identifying the signaling mechanisms by which BE exerts its anti-inflammatory effects.