Health Effects of Indoleamines in the Prevention of Cognitive Decline Associated with Brain Aging and Age-Related Diseases

Abstract

[eng] Tryptophan (TRP) has been linked to the immune response mainly through the immunosuppressive activities of indoleamine 2, 3-dioxygenase (IDO). Here we show evidence that TRP acts as a biochemical signal from damaged cells that attracts and enables immune responses. TRP levels above 2-3mol/L are essential for T-Lymphocyte proliferation, but it has never been previously established whether normal physiological levels of TRP are sufficiently low to limit T-Lymphocyte proliferation. Although blood plasma TRP in humans varies from 30 to 65mol/L, most of this TRP is bound to protein so free-TRP levels are much lower. Interstitial fluid levels of drugs and metabolites are generally regarded as being similar to plasma free-levels. Human cerebrospinal fluid (CSF) TRP levels vary from 0.9 to 3.3mol/L in non-inflammatory conditions, but albumin is also present at levels of 1.5 to 5.2mol/L and able to bind TRP in a 1 : 1 ratio. Using ultrafiltration, we measured free TRP levels in CSF from 10 non-inflammatory patients and found these were 22% lower than total TRP in these same patients. This indicated a normal reference interval of 0.5 to 2.9mol/L for CSF free-TRP which is either below or bordering upon the threshold for T-Lymphocyte proliferation previously determined in tissue culture medium. We also measured free TRP in 4 patients with central nervous system inflammatory disease and found free-TRP levels of 0.5+/-0.3 which were well below the threshold. Activated T-lymphocytes in inflammatory conditions release -interferon, which induces IDO in a wide range of different cells including epithelial cells, fibroblasts, dendritic cells, neurones, astrocytes, microglia, trophoblasts and macrophages. IDO is able to lower TRP levels below the threshold for T-lymphocyte proliferation, thus acting as a TRP noise suppression system and feedback control mechanism. Here we show that neutrophils exhibit strong TRP chemotaxis, migrating towards higher TRP levels, which raises the possibility that other myeloid and lymphoid cells might also migrate in a TRP gradient. We observed that freeze-thaw damaged liver tissue slices or fresh slices incubated with Staphylococcus aureus or Escherichia coli produce very large quantities of TRP along with other amino acids. We propose that the TRP signal arises from damaged tissue, raising TRP levels well above the threshold for T-lymphocyte proliferation, that IDO dampens signal noise by removing excess TRP, highlighting inflammatory foci, maintaining a TRP gradient for inward chemotaxis of neutrophils and possibly other immune cells.