Procalcitonin and its Component Peptides in Systemic Inflammation: Immunochemical Characterization

BACKGROUND: The systemic inflammatory response syndrome (SIRS) is a marked, generalized response to a variety of injuries, if infection is implicated, the term "sepsis" is used. Systemic inflammatory response syndrome/sepsis, which is initiated by proinflammatory cytokines, has been found to be associated with increased serum levels of the prohormone of calcitonin, procalcitonin (ProCT) and its aminoterminus peptide (nProCT). The serum levels of ProCT and nProCT are very useful markers for SIRS/sepsis, and may be used to follow the course, the response to therapy, and/or the prognosis. We studied the serum levels and distribution of ProCT and its component peptides in normal persons for comparison with similar immunochemical and separatory studies in patients with neuroendocrine cancer and with SIRS/sepsis of various etiologies. METHODS: We studied pooled and extracted serum of 13 normal subjects, and sera of patients with neuroendocrine cancer and SIRS/sepsis, using region-specific immunoassays, gel filtration, and high performance liquid chromatography. RESULTS: Normal sera contained small but measurable levels of the intact ProCT molecule, nProCT, a conjoined calcitonin-calcitonin carboxyterminal peptide (CT:CCP-I), CCP-I, free mature CT, and calcitonin gene-related peptide (CGRP). Sera from neuroendocrine cancer usually contained high levels of these peptides. In such cases, free mature CT was always increased, the mean ratio of the intact ProCT to free CT being 168 +/- 68. Gel filtration and HPLC studies of patients with SIRS/sepsis revealed markedly increased levels of ProCT, nProCT, and CT:CCP-I in varying proportions. Mature CT was normal to minimally elevated. The ratio of ProCT to free CT was 2,900 +/- 800. Although serum CGRP is commonly increased in neuroendocrine cancer, it was very low or undetectable in SIRS/sepsis. CONCLUSIONS: These studies indicate that ProCT and its component peptides circulate in normal persons. The serum of patients with SIRS/sepsis contains greatly increased levels of ProCT, nProCT and often, CT:CCP-I. However, in this condition, post-translational processing is incomplete, resulting in mature CT levels that are normal or minimally elevated. In contrast, patients with neuroendocrine cancer have considerably high mature CT levels. Interestingly, although serum CGRP levels often are high in neuroendocrine cancer, they are low in SIRS/sepsis. The marked hyperprocalcitonemia of SIRS/sepsis is probably a consequence of the pro-inflammatory cytokine cascade, and appears to be secreted in a constitutive fashion; the cell(s) of origin of this remarkable hypersecretion is unknown. There is a very marked positive correlation between serum levels of ProCT and nProCT, and the lower level of sensitivity for nProCT may make its measurement a more useful marker for early or mild SIRS/sepsis.