5-Lipoxygenase Deficiency Diminishes TH2 Cell, Regulatory T-Cell and Dendritic Cell Infiltration of Murine Intestinal Polyps
Joseph D. Phillips*1, Mohammad W. Khan3, Eric C. Cheon2, Paul Grippo1, Khashayarsha Khazaie3, David J. Bentrem1,4
1Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL; 2Surgery, Mount Sinai Hospital, Chicago, IL; 3Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, IL; 4Surgery, Jesse Brown VA Medical Center, Chicago, IL
Background: 5-Lipoxygenase (5LO) is an essential enzyme in arachidonic acid metabolism. Overexpression of 5LO has been demonstrated in a variety of cancers, including colon cancer, as well as adenomatous polyps. As such, it is a potential therapeutic target. Direct inhibition of 5LO resulted in decreased proliferation in colon cancer cell lines and inhibited tumor growth in a colon cancer xenograft model. Furthermore, mast cells in particular utilize 5LO to potentiate the proliferation of intestinal epithelial cells and mobilize myeloid-derived suppressor cells (MDSCs), which are known to directly suppress anti-tumor immunity. Recently, our lab has shown that deletion of 5LO profoundly attenuates polyp development in the APCΔ468 murine model of polyposis. Moreover, deletion of 5LO in the bone marrow of mice mitigated the recruitment of MDSCs to the spleen, mesenteric lymph nodes, and tumor site and reduced arginase-1 activity. In this study, we investigate the effect of the 5LO deletion on the tumor inflammatory microenvironment and polyposis. Methods: APCΔ468/5LO+/+ mice were crossed with 5LO-/- mice to generate an APCΔ468/5LO−/− model. All mice were of the C57BL/B6 genetic background. Offspring were genotyped by PCR and sacrificed at 4 months of age. APCΔ468/5LO+/+ mice were compared to APCΔ468/5LO-/- mice using immunoflourescense for Th1 cells (CD8), Th2 cells (CD4), regulatory T-cells (CD4/Foxp3), macrophages (Mac3 and Gr1), and dendritic cells (CD11c and IAb). Results: No statistically significant difference was observed in the infiltration of CD8+ cells between the APCΔ468/5LO+/+ and APCΔ468/5LO-/- groups. However, CD4+, CD4+FoxP3+, and CD11c+IAb+ cell infiltration was significantly reduced (p<0.05) in the polyps of 5LO-deficient mice. Conclusion: Deletion of 5LO results in decreased colorectal polyposis and reduced infiltration of inflammatory cells, including mast cells, MDSCs, Th2 effector cells, regulatory T-cells, and dendritic cells. These results provide further evidence for the inflammatory and tumorigenic role of 5LO and indicate that inhibition of 5LO may provide an effective treatment for colorectal polyposis and cancer.
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