Elsevier

Brain, Behavior, and Immunity

Volume 25, Issue 8, November 2011, Pages 1617-1625
Brain, Behavior, and Immunity

The social environment and IL-6 in rats and humans

https://doi.org/10.1016/j.bbi.2011.05.010Get rights and content

Abstract

Inflammatory cytokine levels predict a wide range of human diseases including depression, cardiovascular disease, type 2 diabetes, autoimmune disease, general morbidity, and mortality. Stress and social experiences throughout the lifecourse have been associated with inflammatory processes. We conducted studies in humans and laboratory rats to examine the effect of early life experience and adult social position in predicting IL-6 levels. Human participants reported family homeownership during their childhood and current subjective social status. Interleukin-6 (IL-6) was measured from oral mucosal transudate. Rats were housed in groups of three, matched for quality of maternal care received. Social status was assessed via competition for resources, and plasma IL-6 was assessed in adulthood. In both humans and rats, we identified an interaction effect; early social experience moderated the effect of adult social status on IL-6 levels. Rats that experienced low levels of maternal care and people with low childhood socioeconomic status represented both the highest and lowest levels of IL-6 in adulthood, depending on their social status as young adults. The predicted interaction held for non-Hispanic people, but did not occur among Hispanic individuals. Adversity early in life may not have a monotonically negative effect on adult health, but may alter biological sensitivity to later social experiences.

Highlight

► Early adversity amplifies the effect of adult social status on IL-6 levels in both humans and laboratory rats.

Introduction

Growing evidence links inflammatory processes to a wide range of human diseases, including depression, cardiovascular disease, type 2 diabetes, and autoimmune disease, as well as general morbidity and mortality. The inflammatory cytokine interleukin 6 (IL-6) has been identified as an important marker of disease risk; elevated levels of IL-6 predict onset of disease, disease progression, and functional decline (Cesari et al., 2003, Ferrucci et al., 1999, Hohensinner et al., 2011, Volpato et al., 2001). Increased levels of salivary IL-6 have been associated with children’s mental health problems, suggesting that even small differences in inflammation early in life can have important health effects (Keller et al., 2010).

Social experiences correlate with inflammatory processes in both human populations and laboratory animals. Inflammatory cytokines, including IL-6, increase in response to acute psychosocial stress (Steptoe et al., 2007) and appear to be elevated under conditions of chronic stress, including low socioeconomic status (SES) (Gimeno et al., 2007, Friedman and Herd, 2010, Loucks et al., 2010), caring for a spouse with dementia (Kiecolt-Glaser et al., 2003), and unemployment (Hintikka et al., 2009). Positive psychosocial resources such as coping and self-esteem inversely correlate with IL-6 levels in both serum and saliva (Sjogren et al., 2006). In mice, social stress can alter immune system functioning (Bartolomucci, 2007), may increase proinflammatory cytokine (IL-6 and TNF-α) production, and can lead to glucocorticoid resistance (Kinsey et al., 2008, Powell et al., 2009). Psychological stress has been found to increase plasma IL-6 in rats (LeMay et al., 1990, Takaki et al., 1994), accompanied by up-regulation of IL-6 gene expression in the brain (Shizuya et al., 1997, Jankord et al., 2010). Stress-induced disruptions in neuroendocrine-immune signaling may lead to increased levels of circulating inflammatory mediators, independent of an acute inflammatory response.

Early-life experience during sensitive periods has the potential to shape developmental trajectories and may have wide-ranging impacts on physiology and behavior. Parental care is a potent source of variability in experience during mammalian development that affects multiple outcomes from stress reactivity to sexual behavior. Aspects of maternal care and offspring characteristics have been studied extensively in rodents, primates, and humans (Levine et al., 1957, Harlow and Zimmermann, 1959, Denenberg et al., 1962, Francis et al., 1999, Fleming et al., 2002, Cameron et al., 2008). The laboratory rat model studying natural variations in maternal care is an extension of the neonatal separation/handling paradigm pioneered by Seymour Levine (and employed by many others) and the primate work of Harry Harlow originating in the 1950’s and 1960’s. This model has helped elucidate a pathway by which variations in maternal care predict differences in behavioral and endocrine responses to stress in the offspring. Data from the rat maternal care paradigm have identified a role for epigenetic processes as mechanistic mediators linking the quality of maternal care received and observed postnatal programming effects. Maternal licking/grooming appears to influence glucocorticoid receptor (GR) density in the hippocampus, at least in part, by differential methylation of the GR promoter in the days after birth (Weaver et al., 2004). These findings suggest that offspring reared in the high-maternal condition possess more tightly regulated stress-axes. This model has broadened understanding of the potential for epigenetic mechanisms, such as DNA methylation, to allow for the biological encoding of experience in ways that affect long-term gene expression (see (Meaney, 2010) for a general review). Relevant to the current paper, no studies have been conducted that explicitly examine the role of early-experience and differential regulation of IL-6 in rats or humans.

The stress-diathesis model of disease would suggest that existing biologic vulnerabilities interact with life experiences or stressors to produce disease or pathology. Recent data across multiple disciplines suggest that early life stressful experiences are actually contributing to the creation or instantiation of biologic vulnerability. For instance, a recent review suggests that the effects of stress on health in adulthood appear more consistent among populations with underlying vulnerability, perhaps induced in response to early life environment (Champagne, 2010). Miller and Chen (2010) found such an interactive effect when examining the relationship between harsh parenting experiences and life stress among adolescent girls. The combination of the two exposures predicted the emergence of a proinflammatory phenotype. Similarly, severe early life stress, such as childhood maltreatment, has been associated with increased inflammatory response to acute psychosocial stress in adulthood (Carpenter et al., 2010).

Animal models have also demonstrated an interactive effect between juvenile and adult environment in predicting inflammation. In an animal model of colitis, neuroendocrine changes and exacerbated symptoms appeared strongest among mice that had also been stressed as juveniles (Veenema et al., 2008). Evidence from animal models employing rhesus macaques and laboratory rats suggest that stress during gestation (Coe et al., 2002) and lipopolysaccharide (LPS, bacterial endotoxin) exposure in the neonatal period (Walker et al., 2009, Walker et al., 2010, Spencer et al., 2011) can lead to long-lasting alterations in cytokine biology and neuroendocrine stress responses. These studies reinforce the paradigm that adult experiences are most potent among those already vulnerable due to early life circumstances. While these examples highlight the interactions of stressful experiences over the lifecourse, they do not directly examine the potential beneficial effects of a positive environment for the more biologically sensitive group.

In the current study, we examine the interaction of social experiences over the lifecourse, characterized across species, using an approach that bears similarities to Boyce and Ellis’ theory of biological sensitivity to context (BSC) and Belsky’s concept of differential susceptibility. Boyce and Ellis propose in a series of elegant papers that, in humans, different early life experiences can prime biological reactivity to later environments. Ultimate health outcomes for an individual depend on both biological sensitivity to context and the quality of later environments, with the highly reactive individuals experiencing both the best and worst outcomes (Ellis and Boyce, 2011, Boyce and Ellis, 2005, Ellis et al., 2005, Ellis et al., 2011). Belsky’s model describes temperament, endophenotypes, and genotypes as factors that can make individuals more responsive to environmental circumstances (Belsky and Pluess, 2009).

Although our questions arise from the field of social epidemiology, human studies face inherent limitations in addressing questions of social experiences over the lifespan. Human studies cannot fully control for all social environments encountered over a lifetime, especially when childhood risks are measured retrospectively. In addition, many risk factors for inflammation are correlated, such as social class, material resources, neighborhood environment, and personal health behaviors. The potential for confounding, both measured and unmeasured, is quite high. When attempting to separate the effects of early life environment and later social status in human studies, researchers face the challenge of including study participants in all combinations of exposure categories and risk violating the assumption of positivity (Westreich and Cole, 2010).

Using animal models in combination with human studies provides a novel approach to understanding how social experiences become biologically embedded across the lifecourse. Animal models provide an opportunity to explore the questions raised by the epidemiologic work in humans. They allow for full characterization of social exposures and control of environmental circumstances; results from animal studies can be used to support correlational evidence in human populations. In the current paper, we present data from conceptually similar studies in college students and laboratory rats to address the relationship between early life environment, social status, and IL-6. Our study utilizes a younger human sample than those often studied, in concert with a cohort of laboratory rats fully characterized with respect to their relative social rank. Our innovative approach to interdisciplinary research combines data from studies in humans and an animal model to explore how early life experience interacts with adult social status to influence levels of IL-6. More generally, we investigate how social experiences that occur over the lifecourse interact to influence markers of inflammation.

Section snippets

Participants

One hundred and twelve participants (70 females, 42 males) were sampled from the student undergraduate population at the University of California, Berkeley. The study was advertised on the UC Berkeley campus; subjects were recruited through the Psychology Department’s Research Participation Program and received partial course credit for participation. Participants ranged from 18 to 33 years of age (mean = 19.6). The sample included 19% Caucasian, 47% Hispanic, 3% African American, and 23% Asian

Results

In the human study, mean OMT IL-6 concentration was 1.34 pg/mL, as shown in Table 1. Participants were all college students, with an average age of 19.6 years. 37% of the participants were male, and 47% were Hispanic. Bivariate correlations between predictor variables are presented in Table 2. Social status was significantly associated with maternal education, depressive symptoms, perceived stress, and age. Home ownership was significantly correlated with maternal education. In the rat study,

Discussion

Results from conceptually similar studies in humans and rats demonstrate a strong interaction between early life experience and adult social status in relation to IL-6 levels, in which early adversity increases sensitivity to adult social status. Our findings suggest that adversity in childhood may not have a monotonically negative effect on later life health, but may alter responsiveness to later exposures.

Although we did not hypothesize differences by ethnicity at the outset, we found that

Acknowledgments

This research was supported by NIH grant R24 MH081797-01, the Greater Good Science Center, and the Russell M. Grossman Endowment. We are grateful to Jeremy Hamilton for his assistance with the laboratory analyses.

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