The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-α by blood monocytes from normal men

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Abstract

Aggression, hostility, and anger significantly predict morbidity and mortality from atherosclerotic cardiovascular disease (ACVD). ACVD is believed to be an inflammatory disease characterized by increased expression of a number of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α. This study examined the relation of aggression, hostility, and anger to monocyte-associated TNF-α expression following lipopolysaccharide (LPS) stimulation. Participants were 62 healthy, non-smoking men (aged 18–45 years). Hostility, anger, verbal, and physical aggression were assessed using the Buss–Perry aggression questionnaire (BPAQ). LPS-stimulated TNF-α expression was determined using dual-color flow cytometry gating for CD14+ cells. After controlling for age, race, education, and alcohol use, scores on the hostility (p = .013), physical aggression (p = .010), and verbal aggression (p = .034) subscales, and the total score (p = .007) on the BPAQ were positively associated with LPS-stimulated TNF-α expression. The results suggest that hostility and aggression are associated with an increased expression of TNF-α, a cytokine implicated in ACVD.

Introduction

Aggression, hostility, and anger (AHA) are independently associated with the development and progression of atherosclerotic cardiovascular disease (ACVD; Matsumoto et al., 1993; Siegman & Smith, 1992; Williams et al., 2000). At this time, it is not well understood how AHA influences ACVD. It has been proposed that the link between ACVD and AHA involves the relation of AHA to behavioral factors, such as increased smoking (Scherwitz & Rugulies, 1992), and physiological mechanisms, such as increased lipids and excessive cardiovascular and neuroendocrine responses to stress (see Siegman & Smith, 1992 for review), that contribute to the atherosclerotic process. However, the current understanding of atherosclerosis emphasizes a response to endo-thelial injury involving inflammatory cells, such as monocytes and T-cells, and the production of various atherogenic cytokines (Ross, 1999). It is thought that inflammation not only characterizes atherogenesis but also contributes to the progression of atherosclerosis (Ross, 1993, 1999). Previous studies have linked hostility and anger to mitogenic responses and number of natural killer (NK) and B-cells (Christensen et al., 1996; Miller, Dopp, Myers, Stevens, & Fahey, 1999; Mills, Dimsdale, Nelesen, & Dillon, 1996), but these cells and their corresponding activities have not been directly implicated in the pathogenesis of ACVD (Schwartz, Valente, & Sprague, 1993). Although other psychosocial risk factors of ACVD, such as major depression, have been linked with increased cytokine expression (Maes, 1999), at this time it is not known whether AHA are associated with inflammatory cellular activities and proinflammatory molecules involved in the pathogenesis of ACVD.

An important proinflammatory cytokine that has been implicated in the pathogenesis of cardiovascular disease is tumor necrosis factor (TNF)-α (Ferrari, 1999). TNF-α is a molecule primarily produced by activated monocytes and macrophages (Vasalli, 1992). TNF-α is released in all stages of the inflammatory process associated with atherogenesis (Ross, 1999; Schwartz et al., 1993). A number of studies have shown that TNF-cx has profound effects on altering endothelial cell function (Langler, Friers, & van Hinsberg, 1991) and promoting the expression of adhesion molecules on endothelial cells that contribute to cellular accumulation at the site of injury (Ikuta, Kirby, Shenton, Givan, & Lennard, 1991). TNF-α triggers the induction of interleukin (IL)-6 (Pang, Gouch, Batey, Clancy, & Cripps, 1994), a multifunctional cytokine that not only plays a central role in inflammation but also predicts future coronary events in initially healthy men (Ridker, Rifai, Stampler, & Hennekens, 2000). TNF-α also promotes the production of acute phase proteins such as C-reactive protein (Richards & Gauldie, 1995), another inflammatory risk factor for cardiovascular disease (Danesh, Collins, Appleby, & Peto, 1998). Not surprisingly, TNF-α production by macrophages is increased in atherosclerotic vessels (Barath et al., 1990), in patients with ACVD (Basaran et al., 1993; Vaddi, Nicoloni, Mehta, & Mehta, 1994), and in asymptomatic individuals with traditional risk factors (Elneihoum, Falke, Helblad, Lindgarde, & Ohlsson, 1997; Mendall et al., 1997). Recently, TNF-α production has also been linked to two well-recognized psychosocial risk factors of ACVD. Relative to individuals living in rural farming areas in India, urban slum dwellers, and middle class urbanites, known to be at an increased risk of ACVD, exhibited higher TNF-α levels (Yudkin, Yajnik, Mohamed-Ali, & Bulmer, 1999). Similarly, major depression has also been linked with TNF-α such that depressed individuals show higher concentrations and greater expression of TNF-α (Maes, 1999). Although preliminary, these latter findings underscore the possibility that other recognized psychosocial risk factors of ACVD, such as AHA, are associated with TNF-α.

The purpose of the current study was to examine the relation of AHA to monocyte-associated TNF-α expression following stimulation by lipopolysaccharide (LPS, Salmonella, Sigma Chemical, St. Louis, MO). Given previous observations, we hypothesized a priori that AHA would be associated with heightened expression of monocyte-associated TNF-α following LPS stimulation.

Section snippets

Methods

Subjects. Participants were 62 healthy, nonsmoking men (ages 18–45 years) in the Raleigh–Durham–Chapel Hill area recruited via advertisements placed in local newspapers and fliers placed throughout the community. Interested individuals were told that the purpose of the study was to examine the relation of various psychological factors to health promotion and disease prevention without identifying which diseases or psychological factors were the focus of the study. Therefore, participants were

Results

Table 1 presents mean and SDs for age and BPAQ scores and distribution for race, alcohol use, and educational status. For the most part, participants were well educated and a minority (22%) of subjects reported regular alcohol consumption. Given the distribution of subjects across race, educational status and alcohol use, we collapsed cells among each of these categories. For race, we compared whites to minorities. For educational status, we grouped individuals with college degrees or more

Discussion

We hypothesized that aggression, hostility, and anger would be associated with an enhanced LPS-stimulated expression of monocyte-associated TNF-α in healthy, non-smoking men. Results of this study were supportive of our hypothesis. Univariate analyses indicated a significant positive correlation between TNF-α expression and aggression, assessed via the BPAQ. Furthermore, results of multivariate regression indicated that aggression significantly predicted LPS-stimulated TNF-α expression even

Acknowledgments

This work was supported by a National Heart, Lung, and Blood Institute grant (Grant HL56105 to E.C.S.). The authors thank Karen Achanzar, Kenneth Young, and the Comprehensive Cancer Center Flow Cytometry Facility, under the direction of Michael J. Cook, Ph.D., for conducting the flow cytometry analyses. Lastly, we wish to thank Melanie Tirronen, Sarah Rush, and Tara Pennington for data collection.

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