Procalcitonin amplifies inducible nitric oxide synthase gene expression and nitric oxide production in vascular smooth muscle cells

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Abstract
Objective Elevated procalcitonin concentrations are found in the course of systemic inflammation caused by bacterial insults, for example, sepsis and septic shock. However, the source of procalcitonin and its role in the inflammatory process are still unknown. In clinical studies, procalcitonin concentrations reflected the severity of sepsis and were predictive of mortality, suggesting that an increased procalcitonin synthesis is detrimental for the host. In contrast, ex vivo and in vitro data report anti-inflammatory effects of procalcitonin that rather may represent a benefit for the septic patient. Design Prospective, controlled, in vitro cell culture study. Setting University research laboratories. Subjects WKY rats. Interventions We investigated whether procalcitonin affects one principal mediator of sepsis, inducible nitric oxide synthase-derived nitric oxide, taking into account the typical 3-hr delay of procalcitonin increase following a bacterial challenge. Vascular smooth muscle cells were incubated with lipopolysaccharide (10 μg/mL), tumor necrosis factor-α (500 units/mL), interferon-γ (100 units/mL), and procalcitonin (1, 10, 100, and 1000 ng/mL). Cells were preincubated with lipopolysaccharide for 90 mins followed by the addition of tumor necrosis factor-α/interferon-γ. In a second set of experiments, procalcitonin was added to these proinflammatory agonists 3 hrs after lipopolysaccharide application. Measurements and Main Results Although no inducible nitric oxide synthase complementary DNA was detectable in unstimulated controls and following single application of procalcitonin, inducible nitric oxide synthase gene expression was induced in cells treated with lipopolysaccharide plus tumor necrosis factor-α/interferon-γ for a total incubation time of 24 hrs. When vascular smooth muscle cells were incubated with procalcitonin in addition to lipopolysaccharide plus tumor necrosis factor-α/interferon-γ, a further stimulation of inducible nitric oxide synthase transcription rate could be detected. Conclusions These results provide evidence that procalcitonin acts as a modulator that augments the inflammatory response triggered by agonists like lipopolysaccharide, tumor necrosis factor-α, and interferon-γ. Although not effective as a single stimulus, it might contribute to the detrimental outcome following excessive activation of the inflammatory cascade.