The immune system: Basic principles and modulation by anaesthetics

Accumulating evidence suggests that anaesthetics can affect the function of immunologically active cells. Anaesthetics like barbiturates, opioids, and benzodiazepines interfere with the unspecific and specific immune response, for example by inhibiting the function of neutrophilic leukocytes, monocytes, "natural killer cells", B- and T-lyrnihocytes. This may lead to a suppression of cell adhesion, chemotaxis, phagocytosis, "oxidative killing capacity,", antigen presentation, production of antibodies, release of cytokines, and proliferation and apoptosis of immunoreactive cells. In contrast to the well-documented association between anaesthetics and immunosuppressive effects in vitro, it is unclear whether these findings are also significant in-vivo. Moreover, the specific molecular mechanisms of the immunomodulating effects of anaesthetics still remain to be identified. Possible targets include accessory, molecules like cellular surface receptors, e.g. the benzodiazepine receptor family, and transcription factors, which play, a major role in the regulation of the immune response. The transcription factor families that are mainly responsible for immune responses are the "Nuclear Factor-kappaB" (NF-kappaB), the "Nuclear Factor of Activated T Cells" (NFAT), and the "Activator Protein-1 (AP-1). Anaesthetics may either directly inhibit DNA binding activity or interfere with the signal transduction pathways leading to the activation of these transcription factors. Potential targets therefore include various kinases, e.g. Inhibitor-kappaB-kinase, Mitogen-Activated Proteinkinase (MAP-kinase), or phosphatases like calcineurin, for example. In addition, anaesthetics may also interfere with and modulate target gene expression, for instance of cytokines, adhesion molecules, or growth factors. Identification of the underlying molecular mechanisms might help to explain and prevent undesirable anaesthetic-mediated imununosuppressive effects, for example the adverse effects of treatment with barbiturates in patients suffering from severe craniocerebral trauma. It may also contribute to the development of new pharmacological strategies for immunosuppressive treatment, e.g. in patients with a systemic inflammatory response syndrome or organ transplants.