Meta-tyrosine modulates the immune response induced by bacterial endotoxins

Abstract

The effectiveness of both, trials aimed at counteracting the sepsis-associated inflammation and anti-tumor vaccines has, up to date, been limited. These limitations may be related to the fact that in sepsis and cancer, the early pro-inflammatory events are followed by compensatory anti-inflammatory mechanisms leading to a generalized immunosuppression that hinders any immunologic therapy against both diseases. Meta-tyrosine (m-Tyr) is a product of oxidative stress present in circulation during the sepsis and cancer-associated pro-inflammatory and immune-competent stages, and, at least in sepsis, its concentration is down-regulated as immune-competence vanishes. Further, exogenously administered m-Tyr inhibited metastatic growth in murine cancer models when a state of immunosuppression is installed. Our results demonstrated that m-Tyr could both prevent the establishment of immunosuppression and rescue the host from an installed immunosuppression induced by lipopolysaccharides (LPS), membrane constituents of Gram - bacteria and main responsible for the sepsis-induced immunosuppression. These effects were paralleled with the capacity of m-Tyr to potentiate the LPS-induced pro-inflammatory effects, to inhibit the anti-inflammatory action of dexamethasone and to prevent both the immunosuppression-associated reduction of splenic lymphocytes and the enhanced expression of programmed death ligand-1 in splenic myeloid cells. Concerning cancer, m-Tyr treatment increased the protective effect of a vaccine directed against a tumor whose metastases were inhibited by m-Tyr, suggesting an improvement of the anti-tumor immune response could contribute to its anti-metastatic activity. In summary, we suggest that m-Tyr may modulate crucial immunologic indicators which could improve the management of diseases, like sepsis and cancer, in which immunosuppression is a major clinical problem.