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.