Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue.

OBJECTIVES: This study examined whether chronic interpersonal stress is associated with cellular markers of inflammation and regulation of these responses by in vitro doses of glucocorticoids in rheumatoid arthritis (RA) patients. The association between these markers of inflammation and fatigue was also tested. METHODS: Fifty-eight RA patients completed up to 30 daily ratings of the stressfulness of their interpersonal relations. Interleukin-6 (IL-6) production was analyzed in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cell cultures with and without varying concentrations of the glucocorticoid hydrocortisone. In addition, plasma levels of IL-6 and C-reactive protein (CRP) were analyzed, and subjective ratings of fatigue and pain were obtained on the day of blood sampling. RESULTS: Multilevel modeling showed that higher chronic interpersonal stress was associated with greater stimulated IL-6 production (p<0.05) as well as greater resistance to hydrocortisone inhibition of IL-6 production (p<0.05). These relations were not accounted for by demographic factors, body mass index, or steroid medication use. Stimulated production of IL-6, in turn, was associated with greater levels of self-reported fatigue, controlling for pain (p<0.05). Neither chronic stress ratings nor fatigue symptoms were related to plasma levels of IL-6 or CRP (ps>.05). CONCLUSIONS: Among RA patients, chronic interpersonal stress is associated with greater stimulated cellular production of IL-6 along with impairments in the capacity of glucocorticoids to inhibit this cellular inflammatory response. Moreover, these findings add to a growing body of data that implicate heightened proinflammatory cytokine activity in those at risk for fatigue symptoms.

Elevated concentrations of nonesterified fatty acids increase monocyte expression of CD11b and adhesion to endothelial cells.

OBJECTIVE: Monocyte proinflammatory activity has been demonstrated in obesity, insulin resistance, and type 2 diabetes, metabolic conditions that are frequently associated with elevated levels of nonesterified fatty acids (NEFA). We therefore tested the hypothesis that NEFA may induce monocyte inflammation. METHODS AND RESULTS: Monocytes exposed to NEFA for 2 days demonstrated a dose-related increase in intracellular reactive oxygen species (ROS) formation and adhesion to endothelial cells. All of these effects were inhibited by the coaddition of antioxidants such as glutathione or butylated hydroxytoluene, by inhibition of ROS generation by NADPH oxidase inhibitors, and by inhibition of protein kinase C, a recognized stimulator of NAPDH oxidase. Monocytes exposed to NEFA also demonstrated a significant increase in CD11b message expression. Stimulation of monocyte adhesion to endothelial cells by NEFA was inhibited by addition of neutralizing antibodies to either CD11b or CD18. Finally, surface expression of CD11b increased significantly on monocytes as measured by flow cytometry, after their incubation with NEFA. CONCLUSIONS: These studies indicate that elevated concentrations of NEFA may enhance integrin facilitated monocyte adhesion to endothelial cells and these effects appear mediated, in part, through activation of NADPH oxidase and oxidative stress.

Immune activation and depression in women with rheumatoid arthritis.

OBJECTIVE: We examined markers of immune activation during periods of stress and depressive symptoms in 45 female patients with rheumatoid arthritis (RA) in comparison to 106 controls with no autoimmune disease. METHODS: Depressive symptoms were recorded, clinician ratings of disease activity were made, and blood was drawn for RA patients and controls at baseline and during a designated stressful week. RESULTS: Counts of T cell subpopulations revealed significant differences between RA and control groups in proportions of CD8 and CD4 cells, with higher CD4 and lower CD8 counts for the RA participants. Significant depression by diagnosis interactions were found, revealing greater CD4 activation among RA patients who were depressed in comparison to other groups. Only marginally significant effects of stress were found on T cell counts. Interleukin 6 (IL-6) concentrations also differentiated groups, with the highest levels of IL-6 observed for depressed RA patients under stress. CONCLUSION: These findings provide new evidence that psychosocial factors play a significant role in autoimmune processes that underlie RA.