Therefore, we chose two different LPS, P. gingivalis LPS and E. coli LPS, as the stimulators in this study to explore the reprogramming of the immune system resulted from endotoxin tolerance, which might take place in the development of periodontal inflammation. Secretion of pro-inflammatory cytokines, including TNF-a, IL1b and IL-6, and chemokine, such as IL-8, is one of the most important strategies utilized by the host to resist periodontal microorganisms. However, an orchestrated balance of proinflammatory cytokine, chemokine and anti-inflammatory cytokine release is critical for an innate immune response sufficient to resist periodontopathic bacteria without excessive damage to periodontal tissues. Endotoxin tolerance is an important protective mechanism, which could lead to the reprogramming of cytokine network to limit immune damage and maintain periodontal homeostasis. Therefore, it might be closely related to the progression of periodontitis. The impaired ability to develop endotoxin tolerance in old persons might be associated with the incontrollable periodontal inflammation. Therefore, endotoxin tolerance is a case of reprogramming and immunomodulation rather than a global downregulation of cytokine expression and function. It is often linked with up-regulated expression of antiinflammatory cytokines, such as IL-10 and TGF-ß, which contribute to the deactivation of monocytes/macrophages and the suppression of pro-inflammatory cytokine production in these cells. Our research indicated the SB431542 side effects higher expression levels of IL-10 in peritoneal macrophages from young mice after second LPS challenges compared with those in middle-aged mice, which might be responsible for the more excellent ability to develop endotoxin tolerance in the younger. Periodontitis is an inflammatory disease resulted from polyinfection and there are many other virulence factors in periodonpathic bacteria than LPS. Therefore, heterotolerance might be more universal than homotolerance in the developmemt of periodontitis. Our results indicated that the heterotolerance was much weaker than homotolerance at the levels of TNF-a, which was consistent with previous research partially, but the interesting finding was that there were no significant differences between homotolerance and heterotolerance at the levels of IL-10, which disclosed the complexity of reprogramming in endotoxin tolerance. Another finding of our study was that there were no effects of aging on the expression levels of TLR2, 4 in murine peritoneal macrophages without any stimulation. Our results are consistent with some previous studies. In Murciano’s researches, no significant differences between aged and young donors were observed on cell surface TLR2, 4 and 6 expression on lymphocytes, monocytes and granulocytes. Similar finding was also reported in paper concerning TLR4 expression on macrophages from older and younger mice. In addition, the decreased secretions of TNF-a and IL-10 by peritoneal macrophages from middle-aged mice stimulated with E.coli LPS or P.gingivalis LPS indicated the impaired functions of TLR2.