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Social Stress Desensitizes Lymphocytes to Regulation by Endogenous Glucocorticoids: Insights from In Vivo Cell Trafficking Dynamics in Rhesus Macaques

From the Department of Medicine (S.W.C.), Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, California; Cousins Center for Psychoneuroimmunology (S.W.C.), UCLA AIDS Institute, Jonsson Comprehensive Cancer Center, UCLA Molecular Biology Institute, Los Angeles, California, and HopeLab Foundation, Redwood City, California; California National Primate Research Center (S.P.M., J.P.C.) and Department of Psychology (J.P.C.), University of California at Davis, Davis, California.

Address correspondence and reprint requests to Steve W. Cole, Department of Medicine (Hematology-Oncology), UCLA School of Medicine, 11-934 Factor Building, Los Angeles, CA 90095-1678. E-mail: coles{at}ucla.edu

Objective: To determine whether chronic social stress can desensitize leukocytes to normal physiologic regulation by endogenous glucocorticoids.

Methods: We analyzed the longitudinal relationship between plasma cortisol levels and peripheral blood lymphocyte counts over 16 monthly assessments in 18 rhesus macaques randomized to recurrent social encounters with a stable set of conspecifics or continually varying social partners (unstable socialization).

Results: Animals socialized under stable conditions showed the expected inverse relationship between plasma cortisol concentrations and circulating lymphocyte frequencies. That relationship was significantly attenuated in animals subject to unstable social conditions. Differences in leukocyte redistributional sensitivity to endogenous glucocorticoids emerged within the first week of differential socialization, persisted throughout the 60-week study period, and were correlated with other measures of glucocorticoid desensitization (blunted hypothalamic-pituitary-adrenal (HPA) axis response to acute stress and redistributional response to dexamethasone challenge). Effects of unstable social conditions on leukocyte sensitivity to cortisol regulation were not related to physical aggression.

Conclusion: Chronic social stress can impair normal physiologic regulation of leukocyte function by the HPA axis in ways that may contribute to the increased physical health risks associated with social adversity.

Key Words: social stress • glucocorticoid resistance • hypothalamic-pituitary-adrenal axis • psychoneuroimmunology • immune system • rhesus macaque

Abbreviations: GR = glucocorticoid receptor; HPA = hypothalamic-pituitary-adrenal; IACUC = Institutional Animal Care and Use Committee; IL = interleukin; SIV = Simian Immunodeficiency Virus.