At the cellular level, immune and inflammatory responses are regulated by cascades of chemical reactions that modify the activity of intracellular proteins and lead to production of pro- or anti-inflammatory hormones (cytokines). In inflammatory bowel disease (IBD), therapy based on use of monoclonal antibodies (Remicade, Humira) directly targets one of these pro-inflammatory cytokines (TNF or tumor necrosis factor) so as to inactivate it.
With this same goal of regulating the effect of these cytokines, another therapeutic strategy consists of intervening early on by inhibiting the cascade of intracellular events which lead to their synthesis. This strategy is the basis for trials using inhibitors of the p38 protein. This protein is directly involved in regulation of pro-inflammatory cytokine production as well as in infiltration of certain immune cells (the lymphocytes) into the intestinal mucosa during the course of IBD. P38 belongs to the family of MAP kinase proteins, the targeting of which is also envisaged during the course of other chronic inflammatory pathologies.
However, this strategy is currently encountering difficulties due to the absence of specificity of the inhibitors being used, thus generating a number of secondary effects and preventing their use in therapeutics. This protein would also appear to have distinct functions depending on the tissue in which it is found, thus explaining why such targeting produced contradictory effects in the different clinical trials during the course of IBD. This was suggested in an article recently published in Gastroenterology, which demonstrated that the p38 protein plays a pro-inflammatory role in certain immune cells (the macrophages) as well as an important role in maintenance of the intestinal barrier in colonic epithelial cells.
The result is that inhibition of this protein indeed decreases inflammation of immune cells, but also leads to a weakening of the intestinal barrier, an event which might be implicated in development of IBD. Identification of such a mechanism would thus enable anticipating this secondary effect by using a molecule such as dibenzazepine, which restores the intestinal barrier, in the framework of therapeutic strategy involving p38 inhibitors. Results published in this article indicate that this association of molecules is effective in regulating intestinal inflammation in experimental models of colitis induced in mice. Such a strategy could be envisaged so as to improve results of clinical trials on p38 inhibitors in humans.
Distinct Effects of p38a Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel Disease, MOTOYUKI OTSUKA, YOUNG JUN KANG, JIANLIN REN, HUIPING JIANG, YINBIN WANG, MASAO OMATA and JIAHUAI HAN*, Gastroenterology, in press, 2010
