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The present article proposes tumor-promoting biochemical effects of the immunologically active pteridine-compound neopterin. Based on previous findings of interactions between neopterin and the cellular redox state, two major pathways of tumor progression are presented: (1) the inhibition of nitric oxide-induced apoptotic death of tumor cells via suppression of nitric oxide synthesis in the presence of neopterin; (2) the stimulatory effects of neopterin on the production and release of angiogenic growth factors. High serum neopterin concentrations are a common finding in tumor patients and correlate well with the fatal outcome of the disease. Affection of tumor tissue growth as well as formation of metastases by neopterin may provide an explanation for these clinical observations., (Copyright 2003 Elsevier Science Ltd.)

Personnel working in operating theatres and recovery rooms are exposed to a variety of noxious substances. The results of studies of the effects of occupational exposure on immune parameters are conflicting. Neopterin is an acknowledged marker of immunostimulation. Urinary neopterin levels of 58 anaesthetists and anaesthetic nurses were measured over a 3-week period. Neopterin analyses were performed using high performance liquid chromatography. Neopterin levels were within the normal range for all subjects. Younger subjects (aged < or = 35 years) had significantly higher urinary neopterin concentrations than older subjects (aged > 35 years). The present study is the first to investigate the influence of anaesthetic exposure on neopterin levels. No evidence of immunostimulation was found.

Production and release of proinflammatory mediators such as tumour necrosis factor-alpha and neopterin are common events following the activation of the cellular immune system. Concerning inflammatory disorders of the lung, e.g. sepsis or sarcoidosis, high serum neopterin levels have been reported to correlate well with the severity of the disease. These situations are often associated with an increased expression of ICAM-1 reported to be induced in type II alveolar epithelial cells. In our study we investigated the potential effects of neopterin on ICAM-1 synthesis in the type II-like pneumocyte cell line L2. Detection of ICAM-1 gene expression by reverse transcriptase-polymerase chain reaction revealed a dose-dependent effect of neopterin, with maximum impact following 12-h incubations. Comparable results were obtained when ICAM-1 protein synthesis was measured via a cell-based ELISA. In a second set of experiments we were able to show that coincubation of L2 cells with pyrrolidine dithiocarbamate (PDTC) significantly suppressed neopterin-induced ICAM-1 synthesis. Since PDTC is known to be a potent inhibitor of NF-kappaB, the stimulating effects of neopterin on ICAM-1 gene expression and protein generation may be mediated by activation of this transcription factor. From these data we conclude that neopterin stimulates ICAM-1 production in L2 cells. In vivo, these effects may contribute to the prolongation of the inflammatory response, including cytotoxic cell host defence mechanisms that impair the functions of the airway epithelium.

Numerous studies indicate that proinflammatory substances like tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) as well as macrophage-derived neopterin are increased in atherosclerotic tissue and thus are potentially involved in the process of atherogenesis. Since apoptotic death of vascular smooth muscle cells (VSMC) is reported to occur in atherosclerotic lesions, we investigated the effects of neopterin, TNF-alpha, and IFN-gamma on apoptosis in cultured VSMC. Morphological changes characteristic of apoptosis as well as DNA fragmentation were detected in cells treated with neopterin, TNF-alpha/IFN-gamma, and neopterin + TNF-alpha/IFN-gamma. Simultaneously, neopterin, TNF-alpha/IFN-gamma, and neopterin + TNF-alpha/IFN-gamma led to inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) synthesis. NO generation was significantly reduced when cells were cotreated with the competitive iNOS inhibitor aminoguanidine. This was accompanied by decreased percentual apoptosis as detected by FACS analysis using all kinds of stimuli. We conclude that neopterin as well as TNF-alpha/IFN-gamma are potent mediators of apoptotic death in VSMC which is at least in part triggered by NO synthesis induced by these proinflammatory mediators.

Synthesis and secretion of proinflammatory mediators like tumor necrosis factor-alpha and neopterin are common events in severe systemic inflammatory disorders, e.g. sepsis and septic shock. Recent data suggest that both substances show similarities with respect to their bioactivities. In the present study we investigated the potential interactions of neopterin and tumor necrosis factor-alpha on inducible nitric oxide synthase gene expression and nitric oxide generation in rat vascular smooth muscle cells. In addition, we studied the influence of neopterin on tumor necrosis factor-alpha synthesis in this cell type. Single stimulation of smooth muscle cells with either neopterin or tumor necrosis factor-alpha caused inducible nitric oxide synthase gene expression and nitric oxide production. Coincubation of cells with both compounds resulted in at least additive effects on nitric oxide synthesis. Quantification of tumor necrosis factor-alpha cDNA revealed a dose-dependent effect of neopterin on tumor necrosis factor-alpha gene expression. Similar results were obtained concerning the detection of tumor necrosis factor-alpha protein and the assessment of tumor necrosis factor-alpha bioactivity. These data suggest that neopterin and tumor necrosis factor-alpha are closely associated with regard to synthesis and effects, respectively. The interactions of both inflammatory mediators in vascular smooth muscle cells might contribute to the excessive release of nitric oxide observed during sepsis, thus triggering cellular destruction and multiple organ failure.

Synthesis and secretion of proinflammatory mediators like tumor necrosis factor–α and neopterin are common events in severe systemic inflammatory disorders, e.g. sepsis and septic shock. Recent data suggest that both substances show similarities with respect to their bioactivities. In the present study we investigated the potential interactions of neopterin and tumor necrosis factor–α on inducible nitric oxide synthase gene expression and nitric oxide generation in rat vascular smooth muscle cells. In addition, we studied the influence of neopterin on tumor necrosis factor–α synthesis in this cell type. Single stimulation of smooth muscle cells with either neopterin or tumor necrosis factor–α caused inducible nitric oxide synthase gene expression and nitric oxide production. Coincubation of cells with both compounds resulted in at least additive effects on nitric oxide synthesis. Quantification of tumor necrosis factor–α cDNA revealed a dose–dependent effect of neopterin on tumor necrosis factor–α gene expression. Similar results were obtained concerning the detection of tumor necrosis factor–α protein and the assessment of tumor necrosis factor–α bioactivity. These data suggest that neopterin and tumor necrosis factor–α are closely associated with regard to synthesis and effects, respectively. The interactions of both inflammatory mediators in vascular smooth muscle cells might contribute to the excessive release of nitric oxide observed during sepsis, thus triggering cellular destruction and multiple organ failure. [ABSTRACT FROM AUTHOR]