Although the etiology of inflammatory bowel disease (IBD) is complex, it bears a number of similarities to other inflammatory diseases that are partly mediated by rogue T cells, such as rheumatoid arthritis and pulmonary fibrosis. In some of these other pathologies, it has become clear that the CXCL12 chemokine and its receptor, CXCR4, are important for targeting of both regulatory and effector T cells to the sites of inflammation. Interestingly, because CXCR4 is also a co-receptor for HIV entry into CD4+ T cells, there have been a number of efforts to develop receptor antagonists. These efforts also have spawned new research efforts in the use of CXCR4 antagonists for treatment of other immunologic pathologies. In this issue, the article by Mikami et al. describes a study in IBD patients and in a murine colitis model that sought to determine whether the CXCL12/CXCR4 axis has a role in IBD. It was found that CXCR4 expression in peripheral T cells was increased in patients with ulcerative colitis and that the increases were correlated with disease severity. Increased CXCL12 mRNA levels were also found in colonic mucosal biopsies from IBD patients with active disease. These finding were also seen in the murine colitis model, and selective expression of knocked-in green fluorescent protein-CXCL12 was observed in submucosal lesions. Furthermore, the severity of the pathology in the murine model was ameliorated with a CXCR4 antagonist. In the mouse, it was also found that the antagonist inhibited migration of regulatory T cells into the lesions and proximal tissues. Although a number of interesting questions about the balance of Th1 versus Th2 T cell participation in mediating the inflammatory response remain, these results firmly place the CXCL12/CXCR4 axis in the etiology of IBD and that observation immediately suggests possible therapeutic interventions.
See article at J Pharmacol Exp Ther 2008, 327:383-392.
- The American Society for Pharmacology and Experimental Therapeutics