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
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.
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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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2012, Journal of Reproductive ImmunologyCitation Excerpt :The local and generalized inflammation is thought to be associated with an imbalance of maternal Th1/Th2 response (Saito et al., 1999, 2007; Redman and Sargent, 2007; Darmochwal-Kolarz et al., 2009). Other studies (Sakai et al., 2004; Darmochwal-Kolarz et al., 2007; Toldi et al., 2008; Steinborn et al., 2008) found a deficit of CD4+CD25bright T regulatory cells in peripheral blood of patients with preeclampsia. Santner-Nanan et al. (2009) compared the populations of Treg cells in preeclamptic patients, healthy pregnant, and non-pregnant women with the use of three maker combinations, CD4+CD25high, CD4+FoxP3+ and CD4+CD127lowCD25+.
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2011, Pregnancy HypertensionCitation Excerpt :It was also suggested that IL-18 is expressed at sites of chronic inflammation and that this interleukin can up-regulate cyclooxygenase, inducible nitric oxide synthase and adhesion molecules [38–40]. It is noteworthy that intravascular excessive inflammatory response is thought to be the cause of clinical symptoms and signs of preeclampsia [9,40]. The roles of IL-18 in pregnancies complicated by intrauterine fetal growth restriction with and without preeclampsia are yet to be elucidated.
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2010, Immunology LettersCitation Excerpt :IFNγ levels are suppressed during a normal pregnancy [68] but they increase significantly in preeclampsia. A high IL-18/IL-12 ratio favours a Th2 response during a normal pregnancy, while a low ratio favours a Th1 response, especially of IFNγ, in preeclampsia [99]. Monocyte levels are also elevated during pregnancyo [26], which has been attributed to an increase in the concentration of E2 that induces its release from the bone marrow [100].
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