Unconjugated pteridines and the activation of macrophages by interferon gamma

Abstract

Webber and Nazarbaghi [12] are to be commended for their studies on the t ransport of unconjugated pteridines in C C R F C E M human lymphoblas t ic cells. However, the discussion relating to the occurrence of certain pteridines during the activation of immune response mechanisms deserves some comments. It is now well recognized that among the several pterins excreted, e.g., in human urine, only the concentrat ion of D-erythro-neopterin is associated with act ivated human macrophages, because these cells produce large quantities of neopterin upon induction by interferon gamma, derived from activated T cells [111. A mult i tude of clinically oriented investigations by a mult i tude of research groups have shown that measuring neopterin in human body fluids enables sensitive moni tor ing of a variety of diseases, all being characterized by the involvement of macrophage activation. These issues have recently been reviewed [11]. Important ly , studies conducted on neopterin and biopterin levels in diseases involving macrophage activation have failed to demonstra te a similar association of biopterin with the immune response [21. In contrast, measurements of biopter in derivatives are essential in the rare group of metabol ic diseases caused by failure to synthesize te t rahydrobiopter in , the well-known cofactor of certain monooxygenases , notably, in the differential diagnosis of the variants of atypical phenylketonur ia [3]. It has previously been claimed that 6-hydroxymethylpterin was excreted in raised amounts by tumor cells in culture and was thus suited for clinically relevant discr iminat ion between cancer patients and healthy subjects [8]. Doubts have been raised against this statement, and the original authors themselves corrected their f inding a few years later, report ing that ur inary concentrat ions of 6-hydroxymethylpter in in cancer patients were not different from those in healthy individuals [9]. Rather, the authors noted raised neopter in concentrat ions in urine from cancer patients, in agreement with previous observations of our group [101. Meanwhile, there is agreement that among the pteridines found in human body fluids, neopterin is most consistently raised in certain tumor types [11]. Furthermore, several independent studies [1, 4-7] have demonst ra ted that high neopterin concentrat ions in the urine and serum of cancer patients are significantly associated with a poor prognosis. The suppressed immune responsiveness of cancer patients that can be measured by, e. g., skin test anergy or a reduced in vitro proliferat ive response of T cells, does not exclude the presence of circulating cytokines in these patients. This seems to indicate that a persistent macrophage activation can be found in mal ignant disease. Little is known at present concerning the function of immune response-associated neopter in product ion by human monocytes /macrophages . The not ion of an efficient interferon gammainduced degradat ion of t ryptophan via the kynurenine pathway [13] by induction of indoleamine 2,3-dioxygenase may be helpful for further research on this unresolved question.