Plasma interleukin-6 is associated with psychological coronary risk factors: Moderation by use of multivitamin supplements

Abstract

The current study examined the relation of plasma IL-6 to anger, hostility, and severity of depressive symptoms as a function of multivitamin supplement use in 96 healthy, nonsmoking men (aged 18–46). Plasma IL-6 was independently associated with anger, hostility, and severity of depressive symptoms, as well as with a composite factor score, but only among nonusers. Among users, these associations were not significant. Multivitamin use was associated with lower plasma IL-6 levels, but only among men with high composite factor scores. Statistical adjustments for age, body mass index, resting diastolic blood pressure, fasting total cholesterol, high-density lipoprotein cholesterol, alcohol use, exercise frequency, and educational level did not alter these results. These data suggest that plasma IL-6 is elevated among healthy men characterized by a propensity for anger, a hostile disposition, and greater severity of depressive symptoms and that multivitamin supplements could ameliorate plasma IL-6 levels among these men.

Introduction

It is becoming increasingly clear that interleukin (IL)-6 is an important regulator of the inflammatory process associated with atherosclerotic cardiovascular disease (ACVD) and its clinical sequelae (Ikeda, Ito, & Shimada, 2001; McCarty, 1999; Yudkin, Kumari, Humphries, & Mohamed-Ali, 2000). Prospective studies have shown that higher levels of plasma IL-6 are associated with an increased risk of myocardial infarction (MI) among apparently healthy individuals (Ridker, Hennekens, Buring, & Rifai, 2000a; Ridker, Rifai, Stampfer, & Hennekens, 2000b). Moreover, IL-6 gene transcripts and protein have been detected in human atherosclerotic lesions (Rus, Vlaicu, & Niculescu, 1996; Seino et al., 1994). IL-6 has been shown to elicit the acute-phase response (APR) (Heinrich, Castell, & Andus, 1990) which includes the synthesis of C-reactive protein, a significant predictor of future risk of coronary heart disease in initially healthy men (Koenig et al., 1999; Kuller, Tracy, Shaten, & Meilahn, 1996). Moreover, IL-6 has also been shown to stimulate processes that contribute to atherosclerotic plaque build-up such as: (a) platelet aggregation; (b) production of adhesion molecules by the endothelium; (c) proliferation by vascular smooth muscle cells; and (d) production of tissue factor and monocyte chemotatic protein (MCP)-1 by macrophages (Barton, 1996; Ikeda et al., 2001; Papanicolaou, Wilder, Manolagas, & Chrousos, 1998). Overall, the evidence suggests that IL-6 is not only an important prognostic indicator of risk for clinical events but also a central mediator of inflammatory processes contributing to ACVD.

The significance of IL-6 in ACVD raises the question whether plasma IL-6 is associated with putative psychological risk factors (PRF) of ACVD, such as anger, severity of depressive symptoms, and hostility (Ahmad, 2000; Chang, Ford, Meoni, Wang, & Klag, 2002; Miller, Smith, Turner, Guijarro, & Hallet, 1996; Musselman, Evans, & Nemeroff, 1998; Rozanski, Blumenthal, & Kaplan, 1999; Williams et al., 2000). Evidence suggests that clinical depression and severity of depressive symptoms are associated with elevations in circulating IL-6 (Dentino et al., 1999; Lutgengdorf et al., 1999; Maes et al., 1997; Zorrilla et al., 2001). To date, there have not been any published studies that have examined the relation of anger and/or hostility to plasma IL-6 levels. Although it is possible that severity of depressive symptoms, anger, and hostility are independently associated with IL-6, examining these independent associations does not take into account that anger, hostility, and severity of depression tend to cluster among individuals and that measures of severity of depressive symptoms, anger, and hostility share significant proportion of variance (Felsten, 1996; Raynor, Pogue-Geile, Kamarck, McCaffery, & Manuck, 2002). Given that some studies have shown that combinations of these factors are predictive of both cardiovascular risk factors (Fava, Abraham, Pava, Shuster, & Rosenbaum, 1996) and progression of coronary atherosclerosis in coronary patients (Angerer et al., 2000; Fava et al., 1996), it may be the case that elevations in plasma IL-6 levels also reflect the comorbid presence of anger, hostility, and severity of depressive symptoms.

Although some studies have failed to find a relationship, a number of studies have reported that antioxidant vitamins and the daily use of multivitamins have been linked to reduced morbidity and mortality from cardiovascular disease (Delport et al., 1998; Diaz, Frei, Bita, & Keaney, 1997a; Diaz, Frei, Vita, & Keaney, 1997b; Losonczy, Harris, & Havlik, 1996; Rimm et al., 1993; Rimm et al., 1998; Willet & Stampfer, 2001). Although the precise mechanisms underlying the beneficial effects of vitamins and multivitamin supplements on cardiovascular disease are not known, a number of studies have reported an association between various antioxidant vitamins and IL-6. For example, α-tocopherol has been shown to reduce serum levels of IL-6 in normal volunteers, as well as in persons at high risk for cardiovascular disease (Devaraj and Jialal, 1996, Devaraj and Jialal, 2000; Mol, de Rijke, Demacker, & Stalenhoef, 1997; van Tits, Demacker, de Graaf, Hak-Lemmers, & Stalenhoef, 2000). Similarly, supplementation with vitamin C has been shown to reduce mitogen-stimulated IL-6 production by peripheral blood mononuclear cells (PBMC) (Schwager & Schulze, 1998), as well as circulating levels of IL-6 in men (Woodward, Rumley, Tunstall-Pedoe, & Lowe, 1999). Reduction of IL-6 levels has also been reported with supplementation with vitamin B₁₂ (Yamashiki, Nishimura, & Kosaka, 1992) and vitamin D (Taimi et al., 1993). Thus, the beneficial cardiovascular effects associated with the use of vitamins and multivitamin supplements may be due, in part, to their effects on IL-6.

Whereas some studies have examined the moderating effect of antioxidant vitamins on IL-6 elevations associated with traditional coronary risk factors, such as smoking, diabetes, and hypertriglyceridemia, no study has examined whether the use of vitamin supplements moderates the relation of plasma IL-6 to PRF of ACVD. As with studies of traditional risk factors, it could be that multivitamin supplementation also reduces plasma IL-6 levels among individuals who exhibit PRF for ACVD. Therefore, the current cross-sectional study examined the relation of plasma IL-6 to anger, hostility, and depressive symptoms as a function of multivitamin supplement use in a sample of healthy, nonsmoking men. It was hypothesized that among nonusers, plasma IL-6 would be positively associated with anger, hostility, and severity of depressive symptoms as well as a PRF composite score. Among users of multivitamin supplements, however, it was hypothesized that plasma IL-6 would not be associated with anger, hostility, severity of depressive symptoms, and the PRF composite score.