Elevated serum levels of interleukin-15 and interleukin-16 in preeclampsia

Abstract

A generalized inflammatory response has been considered to be the main pathology and has an important role in the pathogenesis of preeclampsia. The immune aberrations per se and immunomodulatory milieu present in serum need to be elucidated. The purpose of the current investigation was to characterize changes in serum levels of interleukin (IL)-15 and IL-16 in preeclampsia. Thirty-seven women with preeclampsia were recruited and 36 age- and gestational age-matched women with normal pregnancy served as control. Levels of IL-15 and IL-16 were detected with immune assays in all serum samples. We found that serum levels of IL-15 and IL-16 were significantly higher in preeclampsia than in normal pregnancy (p < 0.001 for both). There were significant differences in serum IL-15 and IL-16 between mild and severe preeclampsia (p < 0.01 for both). Our data corroborate the hypothesis of an increased inflammatory response in preeclampsia, as illustrated by the elevated serum levels of IL-15 and IL-16, suggesting their possible role in the pathogenesis of preeclampsia. These associations may offer insight into the pathophysiology of preeclampsia.

Introduction

Preeclampsia, a pregnancy-specific complication occurring in the second half of pregnancy, is characterized by hypertension and proteinuria, and is one of the leading causes for perinatal mortality and morbidity. Despite intense efforts to find the mechanisms and the molecules that induce preeclampsia, no specific etiological factors have been identified. Placental ischemia and endothelial damage have been considered the key pathophysiologies of preeclampsia; however, the mediators leading to these damages have not been clarified (Redman and Sargent, 2005, Roberts and Gammill, 2005). The nature and amounts of the immunoregulatory milieu present in serum may impart insight on in vivo regulation of preeclampsia-associated conditions. Thus, determining cytokine alterations in the serum of women with preeclampsia would be of interest and improve understanding of the etiology and pathogenesis of preeclampsia.

IL-15 was first described as a T-lymphocyte-activating factor with structural homology to IL-2, while IL-16 was initially described as a T-lymphocyte chemoattractant using CD4 as its receptor (Lynch et al., 2003a, Lodolce et al., 2002, Chaouat et al., 2002). Both are pleiotropic cytokines. IL-15 induces T cell proliferation and B cell maturation (Lodolce et al., 2002), and it is especially essential for NK cell development and cytotoxicity (Becknell and Caligiuri, 2005, Carson et al., 1994). IL-16 stimulates the production of proinflammatory cytokines such as IL-6, tumor necrosis factor alpha (TNF-α), IL-1 alpha and IL-15 by monocytes, and upregulation of IL-2 receptor alpha (IL-2R alpha) on T cells (Mathy et al., 2000, Wilson et al., 2004). In addition, IL-16 inhibits IL-4 and IL-5 release from T cells and thus impairs Th2 immunity (Pinsonneault et al., 2001).

IL-15 and IL-16 are expressed in numerous normal human tissues and cell types, including activated monocytes, dendritic cells and fibroblasts (Lynch et al., 2003a, Lodolce et al., 2002, Chaouat et al., 2002). The expression of IL-15 and IL-16 by non-immune cells suggests that they may have activities beyond immune system (Lynch et al., 2003a, Lodolce et al., 2002, Chaouat et al., 2002). Their presence at maternal–fetal interface implies roles in pregnancy (Chaouat et al., 2002). However, this is little understood. Clarifying their changes in pregnancy complications such as preeclampsia would enhance our understanding of their role in pregnancy, in addition to gaining insight into the pathogenesis of pregnancy complication.

Preeclampsia is characterized by excessive systemic inflammation and predominance of Th1 immunity relative to normal pregnancy (Redman and Sargent, 2005, Roberts and Gammill, 2005). Circulating inflammatory mediators, including inflammatory cytokines, have been reported to be elevated in preeclampsia. Important roles for NK cells in preeclampsia are emerging as part of the systemic inflammation as well as the type-1 immune bias of preeclampsia (Borzychowski et al., 2005). On the other hand, serum levels of both IL-15 and IL-16 are increased in inflammatory conditions (Jang et al., 2003, Karaki et al., 2005, Liew and McInnes, 2002, Seegert et al., 2001, van Heel, 2006, Seegert and Schreiber, 2002), such as systemic lupus erythematousus, rheumatoid arthritis, allergic diseases, inflammatory bowel disease and Kawasaki disease. In addition, a bias towards Th1 immunity exists in preeclampsia (Saito and Sakai, 2003, Saito et al., 1999), while IL-16 alters the Th1/Th2 balance by inhibiting Th2 immunity (Pinsonneault et al., 2001). These findings strongly suggest that both IL-15 and IL-16 levels may increase in preeclampsia.

The purpose of the current investigation was to determine the serum levels of IL-15 and IL-16 in women with preeclampsia, and to observe the associations of these interleukins with disease severity.