Su, Robin C; Breidenbach, Joshua D; Alganem, Khaled; Khalaf, Fatimah K; French, Benjamin W; Dube, Prabhatchandra; Malhotra, Deepak; McCullumsmith, Robert; Presloid, John B; Wooten, R Mar M; Kennedy, David J; Haller, Steven T
description
We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for , , and . Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers and . Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.
