Overview of procalcitonin in pregnancy and in pre-eclampsia

Abstract

Procalcitonin (PCT), a precursor for calcitonin, is a prohormone involved in the inflammatory processes, which has been poorly studied in the context of pregnancy. During severe inflammation, PCT derives from almost all cell types, including monocytes and parenchymal tissues, making it a good predictive and diagnostic marker of an inflammatory state with rapidly increased serum levels in inflammation or sepsis. In normal pregnancy, PCT is basally expressed at very low level by decidual cells, even if decidual macrophages, which in normal pregnancy are skewed to M2 macrophages, are resistant to lipopolysaccharide (LPS)-induced production of PCT. As PCT increase is associated with an inflammatory state, several research groups investigated whether PCT can be considered a marker of pre-eclampsia, a pregnancy disease characterized by systemic inflammation. The first aim of this review is to summarize what is already known about the tissues synthesizing PCT, about the stimuli that cause the increase of circulating PCT levels and how PCT acts as a proinflammatory stimulus by itself. Secondly, we will describe the role of this prohormone in normal pregnancy and in pregnancies complicated by pre-eclampsia, highlighting the involvement of the decidual macrophages and the proinflammatory cytokine tumor necrosis factor-α in the modulation of PCT expression in the decidual microenvironment.

Keywords: TNF-α; macrophages; pre-eclampsia; pregnancy; procalcitonin.

Figure 1

Schematic representation of the gene calcitonin‐related polypeptide alpha‐1 (CALC‐1) and procalcitonin (PCT) synthesis. CT = calcitonin; NT‐PCT = N‐terminal PCT; KCT = katacalcitonin. PCT mRNA is produced by alternative splicing of the same gene of calcitonin gene‐related peptide (CGRP). mRNA translation leads to the synthesis of a protein of 141 amino acids, named pre‐PCT, that is cleaved in PCT.

Figure 2

Secretion and biological function of procalcitonin (PCT) in physiological and pathological pregnancy. In healthy conditions PCT is produced mainly in thyroid C cells from the calcitonin‐related polypeptide alpha‐1 (CALC‐1) gene, but almost all the PCT formed in these cells are converted to calcitonin (CT) so that no PCT is released into the circulation. During normal pregnancy, extravillous trophoblast and decidual stromal cells start to synthesize PCT under physiological conditions, but the presence of this prohormone is destined to remain confined in the microenvironment; probably only a very little amount of this decidual PCT is able to reach the circulation contributing to the small increase of PCT serum level in pregnancy. During sepsis PCT is produced mainly by two alternative mechanisms; direct pathway induced by bacterial endotoxins [lipopolysaccharide (LPS)] or other toxic metabolite from microbes, and indirect pathway induced by various proinflammatory cytokines such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6 and IL‐8. Pre‐eclampsia is a pathological condition of the pregnancy characterized by an increase of circulating proinflammatory cytokines that can induced directly an augmentation of PCT.

Figure 3

Model of procalcitonin (PCT) synthesis by decidual cells in normal conditions and in pre‐eclampsia. Decidual stromal cells (DSC), extravillous trophoblast (EVT) and macrophages (M) are able to produce PCT in decidua, but the contribution of M in pathological conditions is the most relevant (right panel), while in normal conditions pregnancy hormones block the macrophage response to lipopolysaccharide (LPS) in terms of PCT production (left panel). Tumor necrosis factor (TNF)‐α is necessary for the up‐regulation of PCT induced by pre‐eclamptic sera on macrophages, but it probably requires co‐operation with additional factors, still to be identified.