RESUMEN
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3ß; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. METHODS: We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3ß-deficient; ΔßΔß) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. RESULTS: Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔßΔß transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. CONCLUSIONS: Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.
RESUMEN
Cysticercosis is an infection of tissues with the larval cysts of the cestode, Taenia solium. While live parasites elicit little or no inflammation, dying parasites initiate a granulomatous reaction presenting as painful muscle nodules or seizures when cysts are located in the brain. We previously showed in the T. crassiceps murine model of cysticercosis that substance P (SP), a neuropeptide, was detected in early granulomas and was responsible for promoting granuloma formation, while somatostatin (SOM), another neuropeptide and immunomodulatory hormone, was detected in late granulomas; SOM's contribution to granuloma formation was not examined. In the current studies, we used somatostatin knockout (SOM(-/-)) mice to examine the hypothesis that SOM downmodulates granulomatous inflammation in cysticercosis, thereby promoting parasite growth. Our results demonstrated that parasite burden was reduced 5.9-fold in SOM(-/-) mice compared to WT mice (P < 0.05). This reduction in parasite burden in SOM(-/-) mice was accompanied by a 95% increase in size of their granulomas (P < 0.05), which contained a 1.5-fold increase in levels of IFN-γ and a 26-fold decrease in levels of IL-1ß (P < 0.05 for both) compared to granulomas from WT mice. Thus, SOM regulates both parasite burden and granulomatous inflammation perhaps through modulating granuloma production of IFN-γ and IL-1ß.
