The proposed research will investigate the role of alpha-1 and beta-2 adrenergic receptor subtypes in increased inflammation in patients with major depression (MD) and varying levels of early life stress. Activation of the innate immune system may play a role in MD and may contribute to the detrimental impact of MD on the development and outcome of medical illnesses including cardiovascular disease, diabetes and cancer. Stress, a well-known precipitant of MD, also activates the innate immune system, and an exaggerated inflammatory response to stress is seen in patients with MD and early life stress. Studies have shown that stress-induced increases in inflammatory responses are mediated in part through the release of catecholamines and stimulation of alpha-1 adrenergic receptor subtypes. In contrast, beta-adrenergic receptor subtypes have been shown to inhibit inflammatory responses. The applicant's preliminary data indicate that inflammatory stimuli upregulate mRNA expression of the alpha-1D adrenergic receptor and downregulate mRNA expression of the beta-2 receptor in a human monocytic cell line, THP-1. The long-term objectives of the proposed research are to further elucidate the mechanisms that contribute to increased inflammation in major depression and early life stress. The primary hypothesis is that chronic exposure to inflammation (and/or stress) will change the relative expression of alpha-1 and beta-2 adrenergic receptors, ultimately leading to an increased sensitivity to catecholamine-induced inflammation. To test this hypothesis, the following specific aims are proposed:
Aim 1) to measure the effect of inflammatory stimuli on alpha-1 and beta-2 adrenergic receptor expression in vitro and determine the inflammatory signaling pathways involved, Aim 2) to determine the impact of inflammatory-induced changes in adrenergic receptor expression on inflammatory responses to adrenergic agonists in vitro, and Aim 3) to examine the relationship between adrenergic receptor expression and inflammatory responses at baseline and following a psychosocial stressor in patients with MD and healthy controls.
In Aim 1, THP-1 cells will be treated with lipopolysaccharide (LPS), and adrenergic receptor mRNA and protein expression will be evaluated using RT-PCR and Western blot. The role of relevant inflammatory signaling pathways in observed effects will be explored using pharmacological antagonists and gene-targeted siRNA.
In Aim 2, adrenergic agonists will be administered to THP-1 cells after LPS treatment, and markers of inflammation (e.g., interleukin-6 [IL-6], nuclear factor kappa beta [NFkB]) will be assessed.
In Aim 3, adrenergic receptor subtype mRNA and protein expression in healthy controls and depressed patients with varying levels of early life stress will be measured and correlated with inflammatory markers (e.g., plasma IL-6 and peripheral blood mononuclear cell NFkB) before and after exposure to a psychosocial stressor. This proposal will provide insights into possible mechanisms linking inflammation to MD and will help identify molecular targets related to the sympathetic nervous system contributions to the relationship among stress, depression and disease.

Public Health Relevance

Project Narrative Increased inflammation is emerging as a possible cause of major depression and may account for the high prevalence of depression in a variety of medical disorders. The goal of the proposed research is to investigate the mechanisms of increased inflammation in major depression with an emphasis on the role of the sympathetic nervous system, catecholamines, and their receptors. The information gained may reveal specific receptor subtypes and signaling pathways that may contribute to an increased sensitivity to catecholamine- induced inflammation in depressed patients, thus revealing novel targets for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Dissertation Award (R36)
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Special Emphasis Panel (ZMH1-ERB-P (02))
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Rubio, Mercedes
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Emory University
Schools of Medicine
United States
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