CFTR mutations impart elevated immune reactivity in a murine model of cystic fibrosis related diabetes

Abstract

Increased life expectancy in cystic fibrosis (CF) is accompanied by an increasing incidence of CF related diabetes (CFRD). Altered immune reactivity occurs in CF, which we hypothesize, is exacerbated by hyperglycemia. Cystic fibrosis transmembrane conductance regulator deficient (CFTR−/−) mice were rendered hyperglycemic by streptozotocin (STZ) to test this hypothesis. CFTR−/−, C57BL/6J, and FVB/NJ mice received either STZ or lactated ringers (LR) ( n = 5–10). Four weeks later, splenocytes were harvested, mitogen stimulated, and analyzed for cytokine production (IL-2, IL-4, and IL-10) along with stimulation indices (SI). SI of STZ-treated CFTR−/− were elevated compared to LR-treated mice, although both were greater than C57BL/6J and FVB/NJ ( p < 0.05). Fasting glucose levels of STZ-treated CFTR−/− mice correlated with SI ( p < 0.003). Stimulated IL-10 concentrations were elevated in STZ-treated CFTR−/− compared to LR-treated animals and controls ( p < 0.05). IL-2 levels were greater in CFTR−/− mice compared to controls ( p < 0.05), but unrelated to STZ. Reinforcing generalized cytokine up-regulation in CFTR−/−, IL-4 levels were greater in CFTR−/− mice compared to C57BL/6J, but FVB/NJ mice demonstrated greatest concentrations following STZ. These results suggest that, hyperglycemia may exacerbate the clinical course in CF by impacting immune reactivity. There is clear need to maximize metabolic management in CFRD.