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Inflammation and immune activation are crucially involved in the pathogenesis of atherosclerosis and cardiovascular disease. Accordingly, markers of inflammation such as fibrinogen, ferritin, C-reactive protein or neopterin are found in patients with vascular diseases, correlating strongly with the extent of disease and predicting disease progression. Neopterin formation by human monocyte-derived macrophages and dendritic cells is induced by the pro-inflammatory cytokine interferon-gamma, which is released by activated T-lymphocytes. Human macrophages are centrally involved in plaque formation, and interferon-gamma and macrophages are also of importance in the development of oxidative stress for antimicrobial and antitumoural defence within the cell-mediated immune response. Interferon-gamma also stimulates the enzyme indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine. Again, macrophages are the most important cell type executing this enzyme reaction, but also other cells like dendritic cells, endothelial cells or fibroblasts can contribute to the depletion of tryptophan. Likewise, enhanced tryptophan degradation was reported in patients with coronary heart disease and was found to correlate with enhanced neopterin formation. In chronic diseases such as in cardiovascular disease, biochemical reactions induced by interferon-gamma may have detrimental consequences for host cells. In concert with other pro-inflammatory cytokines, interferon-gamma is the most important trigger for the formation and release of reactive oxygen species (ROS). Chronic ROS-production leads to the depletion of antioxidants like vitamin C and E and glutathione, with a consequence that oxidative stress develop. Oxidative stress plays a major role in the atherogenesis and progression of cardiovascular disease, and it may also account for the irreversible oxidation of other oxidation-sensitive substances like B-vitamins (e.g. folic acid and B12). They are essential cofactors in homocysteine-methionine metabolism. Associations between moderate hyperhomocysteinaemia and cellular immune activation are found in several diseases including coronary heart disease, and data indicate that hyperhomocysteinaemia may develop as a consequence of immune activation. Homocysteine accumulation in the blood is established as an independent risk factor for cardiovascular disease. Homocysteine itself has the capacity to further enhance oxidative stress. Interferon-gamma appears to be a central player in atherogenesis and in the development and progression of cardiovascular disease. Anti-inflammatory and immunosuppressive treatment (e.g. with non-steroidal anti-inflammatory drugs or statins) may among other consequences, also contribute to a slow-down of the adverse effects of interferon-gamma.

Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1 ؊/؊ -deficient mice. In the caput epididymis of Ido1؊/؊ animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.Indoleamine 2,3-dioxygenase (IDO) 3 (EC 1.13.11.42) is the first and rate-limiting enzyme in Trp catabolism through the kynurenine pathway (Fig. 1). IDO is a ubiquitously expressed cytoplasmic protein typically activated by interferons (IFNs) (1-5). There is ample evidence that IDO mediates potent immunosuppression in classical immune responses as well as in fetal tolerance, tumor immune resistance, and regulation of autoimmune responses (1-3, 6 -8).Thirty years ago, Yoshida et al. (9) reported that rodent epididymal protein extracts exhibited a high IDO activity. Later, Takikawa et al. (10) demonstrated that unlike the classical cytokine-mediated expression of IDO encountered in nearly all mammalian tissues, the epididymal expression of IDO was constitutive and independent of IFN-␥. More recently, we have shown that IDO is expressed in a regionalized manner by both the principal and the apical cells of the most proximal epididymal region, the caput epididymis. To gain insights into the functions of IDO and the intermediates of the kynurenine pathway in the physiology of the mammalian epididymis, we measured the expression of IDO and related enzymes as well as the abundance of kynurenines and other Trp metabolites in both wild type (WT) and Ido1 Ϫ/Ϫ male mice. These data were correlated with light and electron microscopic analyses of epididymal epithelium, sperm count, sperm morphology, and fertility.

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