The genome of vertebrates contains endogenous retroviruses (ERVs) that are largely nonfunctional relicts of ancestral germline infection by exogenous retroviruses. However, in some mouse strains ERVs are actively involved in disease. Here we report that nucleic acid-recognizing Toll-like receptors 3, 7, and 9 (TLR 3, TLR7, and TLR9) are essential for the control of ERVs. Loss of TLR7 function caused spontaneous retroviral viremia that coincided with the absence of ERV-specific antibodies. Importantly, additional TLR3 and TLR9 deficiency led to acute T cell lymphoblastic leukemia, underscoring a prominent role for TLR3 and TLR9 in surveillance of ERV-induced tumors. Experimental ERV infection induced a TLR3-, TLR7-, and TLR9-dependent group of "acute-phase" genes previously described in HIV and SIV infections. Our study suggests that in addition to their role in innate immunity against exogenous pathogens, nucleic acid-recognizing TLRs contribute to the immune control of activated ERVs and ERV-induced tumors.

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The aim of the work was to study whether or not 11-keto-β-boswellic acids prevent induction of autoimmune reactions, insulitis, and hyperglycemia in the model of multiple low-dose streptozotocin (MLD-STZ) diabetes. Using male mice (n = 6) diabetes was induced by daily i.p. injections of 40 mg/kg STZ for 5 days. In a second series together with STZ, daily i. p. injections of 11-keto-β-boswellic acid (KBA) and O-acetyl-11-keto-β-boswellic acid (AKBA) (7.5 and 15.0 mg/kg) were applied for 10 days. Thereafter, pro-and anti-inflammatory cytokines in the blood, histochemistry of pancreatic islets, and blood glucose levels were assayed. Five days after the last injection of STZ, a significant burst of pro-and anti-inflammatory cytokines in the blood, infiltration of lymphocytes (CD3) into pancreatic islets, and appearance of peri-insular apoptotic cells were observed. Plasma glucose increased significantly (124.4 ± 6.65 vs. 240.2 ± 27.36 mg/dl, p <0.05). Simultaneous treatment with KBA and AKBA significantly reduced pro-and anti-inflammatory cytokines (IFN-γ p < 0.01, p < 0.01; IL-1A p < 0.001, p < 0.001; IL-1B p < 0.001, p < 0.001; IL-2 p < 0.001, p < 0.001; IL-6 p < 0.01, p < 0.001; TNF-α p < 0.05, p < 0.001; IL-4 p < 0.01, p < 0.001; IL-10 p < 0.001, p < 0.001) in the blood. No infiltration of lymphocytes into pancreatic islets and appearance of peri-insular cells were detected. Moreover, KBA and AKBA reduced STZ-mediated increase of blood glucose on day 10 to 163.25 ± 16.6 (p < 0.05) and 187.6 ± 19.5 mg/dl (p < 0.05), respectively. In the model of MLD-STZ induced diabetes KBA and AKBA prevent cytokine burst, development of insulitis and reduce increase of blood glucose through "silencing" a forced-up immune reaction.

11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that - similar to the model of MLD-STZ-diabetes - also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.