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Abstract

We greatly appreciate these comments regarding our recent work and share the enthusiasm of Drs Theiss, Merlin, and Sitaraman regarding the long-term potential of these mechanistic insights to lead to improved therapeutic approaches. As we see it, there are several critical issues that must be addressed before we can move forward into clinical trials. For example, the potential side effects of MLCK inhibition may be significant; MLCK is central to many critical biological functions, including intestinal epithelial wound closure (Gastroenterology 2005;28:987–1001). It will also be important to dissect the role of MLCK in chronic disease. Although our work and that of others has shown that MLCK inhibition can acutely restore intestinal epithelial barrier function, these studies have mostly been performed in vitro using cultured cell lines (Am J Physiol Gastrointest Liver Physiol 2006;290:G496–G504; Gastroenterology 1997;113:1873–1882; Gastroenterology 2002;123:163–172) and, even when tissue or in vivo systems were used, analysis was limited to acute effects over several hours (J Clin Invest 2005;115:2702–2715). Other than our study (Lab Invest 2006;86:191–201), no previous work has suggested a role for MLCK in chronic disease. Although increased MLCK expression and activity in active disease is striking, it should be emphasized that, at present, this is a correlative observation; the question of whether increased MLCK expression and activity is a cause or result of inflammation remains unanswered. We have proposed that either can come first, depending on the initial stimulus, but that they are linked in a self-amplifying cycle of disease (Lab Invest 2004;84:282–291). Because we found that, in patients, increases in MLCK expression and activity paralleled disease activity, one might conclude that inflammation causes these increases. This is consistent with the observation that TNF can increase MLCK expression (Am J Pathol 2005;166:409–419; J Biol Chem 2006;281:26205–26215; Am J Physiol Gastrointest Liver Physiol 2005;288:G422–G430). Alternatively, the observation that MLCK expression was modestly increased in inactive disease suggests that some degree of increased MLCK expression may precede active inflammatory disease. Thus, unlike the actual “chicken and egg” question, which has apparently been solved in favor of the egg (BBC NEWS 2006; available: news.bbc.co.uk/go/pr/fr/-/2/hi/uk_news/england/nottinghamshire/5019682.stm), the relative primacy of active intestinal inflammation and increased epithelial MLCK expression remains to be determined. Keeping harmful intruders at bay: Insights into the mechanism of barrier dysfunction during inflammatory bowel diseasesGastroenterologyVol. 132Issue 1PreviewBlair SA, Kane SV, Clayburgh DR, Turner J. (Department of Pathology, The University of Chicago, Chicago, Illinois). Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab Invest 2006;86:191–201. Full-Text PDF