Lower expression of Th1-related cytokines and inducible nitric oxide synthase in mice with streptozotocin-induced diabetes mellitus infected with Mycobacterium tuberculosis.
Diabetes mellitus is an important predisposing factor for tuberculosis. The aim of this study was to investigate the mechanism underlying this association using a murine model. Mice with streptozotocin-induced diabetes mellitus were prone to Mycobacterium tuberculosis infection, as indicated by increased numbers of live bacteria in lung, liver and spleen. In diabetic mice, the levels of IL-12 and IFN-gamma in the lung, liver and spleen were lower than those in control animals on day 14 postinfection, while the opposite was true for IL-4 levels in the lung and liver. The expression pattern of inducible nitric oxide synthase (iNOS), in the two mice types was as for IL-12 and IFN-gamma. In addition, peritoneal exudate cells obtained from diabetic mice produced lower amounts of IL-12 and NO than those from control mice, when stimulated in vitro with M. bovis BCG. Spleen cells from diabetic mice infected with M. tuberculosis produced a significantly lower amount of IFN-gamma upon restimulation with purified protein derivatives (PPD) than those from infected nondiabetic mice. Interestingly, addition of high glucose levels (33 mM) to the cultures of PPD-restimulated spleen cells reduced the synthesis of IFN-gamma only in diabetic mice, and not in nondiabetic mice. Finally, control of blood glucose levels by insulin therapy resulted in improvement of the impaired host protection and Th1-related cytokine synthesis. Our results suggest that the reduced production of Th1-related cytokines and NO account for the hampered host defense against M. tuberculosis infection under diabetic conditions.
Yamashiro
S
S
Division of Infectious Diseases, Department of Internal Medicine, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Kawakami
K
K
Uezu
K
K
Kinjo
T
T
Miyagi
K
K
Nakamura
K
K
Saito
A
A
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016207:Cytokines / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008099:Liver / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000032:analysis*; D052247:Nitric Oxide Synthase Type II; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014373:Tuberculin / Q000276:immunology; D014376:Tuberculosis / Q000209:etiology / Q000276:immunology*
D001786:Blood Glucose; D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D014373:Tuberculin; D018664:Interleukin-12; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse