Jennifer E. Graham-Engeland

Salivary markers of inflammation in response to acute stress.

There is burgeoning interest in the ability to detect inflammatory markers in response to stress within naturally occurring social contexts and/or across multiple time points per day within individuals. Salivary collection is a less invasive process than current methods of blood collection and enables intensive naturalistic methodologies, such as those involving extensive repeated measures per day over time. Yet the reliability and validity of saliva-based to blood-based inflammatory biomarkers in response to stress remains unclear. We review and synthesize the published studies that have examined salivary markers of inflammation following exposure to an acute laboratory stressor. Results from each study are reviewed by analyte (IL-1β, TNF-α, IL-6, IL-2, IL-4, IL-10, IL-12, CRP) and stress type (social-cognitive and exercise-physical), after which methodological issues and limitations are addressed. Although the literature is limited, several inflammatory markers (including IL-1β, TNF-α, and IL-6) have been reliably determined from saliva and have increased significantly in response to stress across multiple studies, with effect sizes ranging from very small to very large. Although CRP from saliva has been associated with CRP in circulating blood more consistently than other biomarkers have been associated with their counterparts in blood, evidence demonstrating it reliably responds to acute stress is absent. Although the current literature is presently too limited to allow broad assertion that inflammatory biomarkers determined from saliva are valuable for examining acute stress responses, this review suggests that specific targets may be valid and highlights specific areas of need for future research.

Affective Reactivity to Daily Stressors Is Associated With Elevated Inflammation

OBJECTIVE Inflammation increases the risk of chronic diseases, but the links between emotional responses to daily events and inflammation are unknown. We examined individual differences in affective reactivity to daily stressors (i.e., changes in positive and negative affect in response to stressors) as predictors of inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP). METHODS A cross-sectional sample of 872 adults from the National Study of Daily Experiences (substudy of Midlife in the United States II) reported daily stressors and affect during telephone interviews for 8 days. Blood samples were obtained at a separate clinic visit and assayed for inflammatory markers. Multilevel models estimated trait affective reactivity slopes for each participant, which were inputted into regression models to predict inflammation. RESULTS People who experienced greater decreases in positive affect on days when stressors occurred (i.e., positive affect reactivity) had elevated log IL-6, independent of demographic, physical, psychological, and behavioral factors (B = 1.12, SE = 0.45, p = .01). Heightened negative affect reactivity was associated with higher log CRP among women (p = .03) but not men (p = .57); health behaviors accounted for this association in women. CONCLUSIONS Adults who fail to maintain positive affect when faced with minor stressors in everyday life appear to have elevated levels of IL-6, a marker of inflammation. Women who experience increased negative affect when faced with minor stressors may be at particular risk of elevated inflammation. These findings add to growing evidence regarding the health implications of affective reactivity to daily stressors.

Daily positive events and inflammation: Findings from the National Study of Daily Experiences

BACKGROUND Inflammation is implicated in the development of chronic diseases and increases the risk of mortality. People who experience more daily stressors than others have higher levels of inflammation, but it is unknown whether daily positive events are linked to inflammation. OBJECTIVE To examine the association of daily positive events with 3 inflammatory markers, interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen. METHOD A cross-sectional sample of 969 adults aged 35-86 from the Midlife in the United States Study completed telephone interviews for 8 consecutive evenings. Participants reported positive experiences that occurred over the past 24h. Blood samples were obtained at a separate clinic visit and later assayed for inflammatory markers. Regression analyses evaluated the frequency of daily positive events (defined as the percent of study days with at least 1 positive event) as a predictor of each inflammatory marker. Covariates included information on demographics, physical health, depressive symptoms, dispositional and behavioral factors, and daily positive and negative affect. RESULTS On average, participants experienced positive events on 73% of days (SD=27%). The frequency of daily positive events was associated with lower IL-6 (p<0.001) and CRP (p=0.02) in the overall sample, and lower fibrinogen among women (p=0.01). The association remained for IL-6 in the fully adjusted model, but was no longer significant for CRP and fibrinogen after controlling for household income and race. Effects were more pronounced for participants in the lowest quartile of positive event frequency than for those in the top 3 quartiles, suggesting that lack of positivity in daily life may be particularly consequential for inflammation. Furthermore, interpersonal positive events were more predictive of lower IL-6 overall and lower fibrinogen in women than non-interpersonal positive events. CONCLUSION Daily positive events may serve a protective role against inflammation.

Depressive Symptoms and Momentary Mood Predict Momentary Pain Among Rheumatoid Arthritis Patients

BackgroundAlthough a relationship between mood and pain has been established cross-sectionally, little research has examined this relationship using momentary within-person data.PurposeWe examined whether baseline depressive symptoms and within-person levels of negative and positive mood predicted momentary pain among 31 individuals with rheumatoid arthritis (RA).MethodsDepressive symptomatology was measured at baseline. Mood and RA symptoms were self-reported via ecological momentary assessment five times a day for seven consecutive days. Analyses controlled for gender, age, weekend day, time of day, and experiences of stress.ResultsGreater momentary positive mood was associated with less momentary pain and fewer arthritis-related restrictions; negative mood was associated with more restrictions. Greater depressive symptomatology also predicted more pain and restrictions, an effect which was not accounted for by mood.ConclusionsResults suggest that both depression and mood are uniquely associated with momentary pain; as such, multi-component interventions may provide optimal disease management.

The role of multiple negative social relationships in inflammatory cytokine responses to a laboratory stressor

The present study examined the unique impact of perceived negativity in multiple social relationships on endocrine and inflammatory responses to a laboratory stressor. Via hierarchical cluster analysis, those who reported negative social exchanges across relationships with a romantic partner, family, and their closest friend had higher mean IL-6 across time and a greater increase in TNF-α from 15 min to 75 min post stress. Those who reported negative social exchanges across relationships with roommates, family, and their closest friend showed greater IL-6 responses to stress. Differences in mean IL-6 were accounted for by either depressed mood or hostility, whereas differences in the cytokine stress responses remained significant after controlling for those factors. Overall, this research provides preliminary evidence to suggest that having multiple negative relationships may exacerbate acute inflammatory responses to a laboratory stressor independent of hostility and depressed mood.

Life Satisfaction Across Adulthood in Bisexual Men and Women: Findings from the Midlife in the United States (MIDUS) Study

The number of lesbian, gay, and bisexual (LGB) adults aged 50 and older is projected to reach 5 million in the U.S. by 2030 (Fredriksen-Goldsen, Kim, Shiu, Goldsen, & Emlet, 2015). Older bisexuals experience more negative mental and physical health outcomes when compared to both heterosexuals and other sexual minorities (Fredriksen-Goldsen, Shiu, Bryan, Goldsen, & Kim, 2017). As bisexuals are the numeric majority of sexual minorities in the U.S. (Herbenick et al., 2010), bisexual aging processes are critical to understand if researchers wish to reduce sexual minority health disparities and promote healthy aging. In the current study, we use a national probability sample of adults from the Midlife in the United States (MIDUS) study to assess life satisfaction across an 18-year period. We aimed to identify whether life satisfaction—an indicator of psychological health and well-being—is similar for same-age bisexual, lesbian and gay, and heterosexual midlife individuals, and whether sexual orientation predicts change in life satisfaction across adulthood. Further, we tested whether life satisfaction among bisexuals changes at the same rate and in the same pattern as for lesbian, gay, and heterosexual individuals. Overall, we found a linear pattern of increase in life satisfaction across adulthood. However, when we accounted for sexual orientation, a different pattern emerged for bisexuals. Whereas heterosexuals and lesbian and gay individuals experienced increases in life satisfaction across adulthood, bisexuals’ life satisfaction did not increase over this period. Implications for bisexual health and well-being are discussed.

Insomnia symptoms are associated with elevated C-reactive protein in young adults

Abstract Objective: Insomnia is associated with elevated inflammation; however, studies have not investigated if this relationship is confounded with depression and neuroticism, which are associated with insomnia and inflammation. The current study examined the association of insomnia symptoms with C-reactive protein (CRP) and with interleukin-6 (IL-6), independently and after controlling for depressive symptoms and neuroticism. Design: Fifty-two young adults (mean age = 25.2 ± 3.9 years, 52% female) completed a baseline survey to assess psychological characteristics, followed by a plasma blood draw. Main outcome measures: Plasma CRP and IL-6. Results: When examined alone, insomnia symptoms were significantly associated with elevated CRP (β = 0.52; R2 = 0.27), as was neuroticism (β = 0.41, R2 = 0.17), but not depressive symptoms (β = 0.21, R2 = 0.05). The association between insomnia symptoms and CRP remained significant when depressive symptoms and neuroticism were entered into the model simultaneously; this model did not explain more variance than the model with insomnia symptoms alone. No variables were associated with IL-6. Conclusions: Results suggest that insomnia symptoms are independently associated with elevated CRP in young adults, even after controlling for presumed overlapping psychological constructs. Findings highlight the potential importance of treating insomnia to reduce systemic inflammation.

Emotional State Can Affect Inflammatory Responses to Pain Among Rheumatoid Arthritis Patients: Preliminary Findings:

In a novel pilot study, we investigated how emotional state is related to inflammatory responses to acute pain among women with rheumatoid arthritis. Nine women completed four 5-hour visits that varied only by manipulation of emotion (anger, sadness, happiness, vs. control); in each visit, acute pain was elicited, with blood draws at baseline, 10 minutes, 60 minutes, and 100 minutes post-pain. We examined the effects of within-subjects factors on circulating inflammatory biomarkers interleukin (IL)-6, IL-10, tumor necrosis factor-α, C-reactive protein, and cortisol. There was a main effect of state anger on IL-6, with higher reported anger associated with higher IL-6 across conditions. Further, there were several interactions between state emotion and condition. For example, when individuals reported higher state anger in the sadness condition compared to their own average, they showed higher levels of IL-6 and cortisol. Findings are discussed within a larger literature suggesting that mixed emotional states can contribute to psychological stress and inflammatory responses.

Distinct inflammatory response patterns are evident among men and women with higher depressive symptoms

Extensive research links depression and inflammation, with emerging evidence suggesting some differences between males and females in these associations. However, relatively few studies have examined stimulated inflammatory responses (ex vivo) in depression. The present research investigated the associations between depressive symptoms, basal inflammation, and LPS-stimulated production of pro- (IL-1β, IL-6, IL-8, TNF-α) and an anti-inflammatory cytokine (IL-10), with a focus on the extent to which gender moderates these relationships. As part of a larger study, 162 socio-economically and racially diverse subjects (ages 25-65, 67% women) completed extensive self-report measures, including depressive symptoms. Whole blood was quantified for basal inflammation, or incubated with 1μg/mL lipopolysaccharide (LPS) for 2h (at 37°C, 5% CO2) to quantify inflammatory responses to bacterial challenge. We examined the associations between depression and inflammatory markers in regression analyses, controlling for age, BMI, race/ethnicity, income, education, and use of medications. No main effects were observed between depressive symptoms and basal or stimulated levels of inflammation. Moderation analyses revealed a significant interaction between depressive symptoms and gender for stimulated TNF-α, stimulated IL-6 (p<0.05), and a marginally significant interaction for stimulated IL-10 (p=0.07). For men, higher depressive symptoms were associated with significantly higher production of TNF-α (p<0.05) and marginally higher IL-6 (p=0.07), but not with the anti-inflammatory cytokine IL-10. For women, higher depressive symptoms were associated with significantly lower production of TNF-α and IL-10 (ps<0.05), and marginally lower IL-6 (p=0.06). These findings provide evidence for gender differences in the association of depressive symptoms with inflammatory response patterns, and highlight the utility of assessing ex vivo immune responses in blood. Implications for health are discussed.

Recalled early life adversity and pain: the role of mood, sleep, optimism, and control

Early life adversity (ELA) has been associated with pain symptomatology in adulthood, but mechanisms and moderators of these associations are unclear. Using recall based and concurrently assessed self-report data, we examined associations between ELA, mood, sleep, and recent pain intensity and interference, and whether optimism and perceived control weakened these associations in a midlife community sample of diverse adults reporting some ELA. Controlling for demographic variables and BMI, higher levels of ELA were associated with more pain intensity and interference; greater sleep disturbance and negative mood accounted for these associations. When moderation was examined, only the path from sleep disturbance to pain interference was significantly attenuated for those with higher optimism and higher perceived control. These findings suggest that higher levels of ELA may link with pain in adulthood through poorer mood and sleep, and that resilience resources such as optimism and control may buffer some of these pathways.