There is immense need for new intervention and prevention strategies against interstitial cystitis (IC), a chronic, relapsing, and severely debilitating disease of the urinary bladder. Estimates indicate that ~1 million cases of IC are reported annually in the United States, with 90% of these occurring in women. In a preliminary study, we showed that, along with acute phase and inflammatory cytokines, serum CXCR3 ligand levels are up-regulated in IC patients as compared with normal healthy donors. Correspondingly, we showed that CXCR3 and its ligands are up-regulated at sites of inflammation in the iliac lymph nodes and urinary bladder following experimental autoimmune cystitis (EAC) induction of chronic IC in mice. We also show that the number of CD4+ T cells, mast cells, and neutrophils is increased at systemic and mucosal sites during chronic IC in mice. Most importantly, we have demonstrated that anti-CXCL10 Abs treatment hinders the development of chronic IC. Urinary bladder CD4+ T cells, mast cells, neutrophil infiltrates, local production of CXCR3 ligand, and systemic Th1 cytokines were also reduced following anti-CXCL10 Abs treatment in mice after chronic IC. These results provide a strong rationale for our central hypothesis, which is to determine whether differential expression of CXCR3 and CXCR3 ligands by hematopoietic, myeloid, and non-hematopoietic cells mediates the induction and progression of IC. Targeting CXCR3 and its ligands may serve as a potential therapeutic option for IC.
Three specific aims will be used to elucidate the precise role of CXCR3 and CXCR3 ligand during IC progression.
We will test the hypothesis that differential expression of CXCR3 and CXCR3 ligand by hematopoietic, myeloid, and non-hematopoietic cells are essential for the induction and progression of interstitial cystitis (IC), targeting CXCR3 and its ligands may serve as a potential therapeutic option for IC. The proposal is innovative and will provide novel information on immune mechanism underlying CXCR3 ligand-mediated amelioration of IC.
