The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients

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Abstract

Interleukin (IL)-18 acts in synergy with IL-12 to promote development of T helper 1 (Th1) responses. On the other hand, IL-18 alone has the capacity to induce Th2 responses. Here, we have measured IL-18 and IL-12 secretion by non-stimulated peripheral blood mononuclear cells (PBMC) from 17 non-pregnant women, 21 healthy pregnant women, 9 mildly pre-eclamptic patients and 15 severely pre-eclamptic patients. Th1/Th2 ratios in PBMC were determined by flow cytometry. PBMC from healthy pregnant subjects secreted more IL-18 and less IL-12 than non-pregnant women. PBMC from severely pre-eclamptic patients secreted more IL-12 than those from healthy pregnant women, while IL-18 secretion in mildly pre-eclamptic patients resembled that in normal pregnancy. The ratios of IL-18 to IL-12 were significantly higher in healthy pregnant women than non-pregnant women. These ratios were significantly lower in severely pre-eclamptic cases than in normal pregnancy subjects, while these ratios in mild pre-eclampsia resembled those in normal pregnancy. Interestingly, Th1/Th2 ratios were negatively correlated with the ratios of IL-18/IL-12. These results suggest that elevated IL-18 secretion and decreased IL-12 secretion by PBMC may induce Th2 dominance in normal pregnancy, while elevated secretion of both IL-18 and IL-12 by PBMC may cause Th1 dominance in severe pre-eclampsia.

Introduction

Cytokine responses are generally characterized as T helper type 1 (Th1) or type 2 (Th2) (Mosman and Coffman, 1989). Recent reports suggested that the pattern of cytokine expression in normal pregnancy is Th2 dominant, which may protect from rejection (Wegmann et al., 1993, Saito et al., 1999a, Tsuda et al., 2001, Michimata et al., 2002). In contrast, pre-eclampsia is associated with a Th1 predominant profile and may be considered as a failure of the tolerance system (Saito et al., 1999b, Saito et al., 1999c; Darmochwal-Kolarz et al., 1999, Ohkuchi et al., 2001, Yoneyama et al., 2002, Wilczynski et al., 2002, Saito and Sakai, 2003).

Interleukin (IL)-18 was originally identified as a circulating molecule in endotoxin-challenged mice following bacterial priming, and was cloned from activated macrophages as interferon (IFN)-γ-inducing factor (Okamura et al., 1995). The synergistic actions of IL-18 and IL-12 are critical for the induction of a Th1 immune response (Okamura et al., 1998), while IL-18 alone has capacity to induce a Th2 immune response (Nakanishi et al., 2001, Nakanishi et al., 2001). These findings suggest that IL-18 and IL-12 may act as regulatory cytokines in normal pregnancy and pre-eclampsia. However, serum IL-18 and IL-12 concentrations in pre-eclampsia are matter of controversy (Dudley et al., 1996, Sacks et al., 1997, Daniel et al., 1998, Ida et al., 2000, Adamas et al., 2003). This discrepancy may be accounted for by the fact that the half-life of circulating cytokines is very short.

Our purpose was to investigate IL-18 and IL-12 secretion by peripheral blood mononuclear cells (PBMC) from healthy pregnant subjects and pre-eclamptic subjects. We also evaluated an association between the ratio of IL-18 to IL-12 secretion and the Th1/Th2 ratios in PBMC.

Section snippets

Subjects

The 24 women with pre-eclampsia chosen for study had gestational onset of hypertension (diastolic pressure exceeding 90 mmHg or systolic pressure exceeding 140 mmHg) and proteinurea (at least ‘++’ by semiquantitative dipstick testing in the absence of urinary tract infection). Pre-eclampsia was classified as mild or severe according to blood pressure; severe pre-eclampsia (n=15) referred to blood pressures exceeding 160/110 mmHg, while mild pre-eclampsia (n=9) referred to blood pressures between

IL-18 and IL-12 production by non-stimulated peripheral blood mononuclear cells

IL-18 concentrations in culture supernatants of PBMC from non-pregnant women, healthy pregnant women, and mild and severe type pre-eclamptic patients were 130±100 pg/ml (range 20–230); 210±110 pg/ml (range 40–430); 200±110 pg/ml (range 70–330); and 160±70 pg/ml (range 50–280); respectively. IL-18 secretion by PBMC in normal pregnant women was significantly higher than that in non-pregnant women (P=0.0238; Fig. 1). IL-18 secretion in mild and severe type pre-eclamptic patients was significantly

Discussion

The present study has examined IL-18 and IL-12 secretion by non-stimulated PBMC in non-pregnant women, normal pregnant women and pre-eclamptic patients. We first reported that IL-18 secretion by PBMC was elevated in normal pregnant women. Although IL-18 mRNA is expressed in a wide range of cells including monocytes/macrophages, Kupffer cells, T cells, B cells, dendritic cells, osteoblasts, keratinocytes and astrocytes, the main producers are monocytes/macrophages (Okamura et al., 1998,

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