Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jun;36(6):995-1003.
doi: 10.1111/j.1530-0277.2011.01685.x. Epub 2011 Dec 5.

A longitudinal analysis of circulating stress-related proteins and chronic ethanol self-administration in cynomolgus macaques

Christa M Helms  1 , Ilhem Messaoudi, Sophia Jeng, Willard M Freeman, Kent E Vrana, Kathleen A Grant
Affiliations

A longitudinal analysis of circulating stress-related proteins and chronic ethanol self-administration in cynomolgus macaques

Christa M Helms et al. Alcohol Clin Exp Res. 2012 Jun.

Abstract

Background: Alcoholics have alterations in endocrine and immune functions and increased susceptibility to stress-related disorders. A longitudinal analysis of chronic ethanol intake on homeostatic mechanisms is, however, incompletely characterized in primates.

Methods: Plasma proteins (n = 60; Luminex) and hormones (adrenocorticotropic hormone [ACTH]; cortisol) were repeatedly measured in adult male cynomolgus monkeys (Macaca fascicularis, n = 10) during a 32-month experimental protocol at baseline, during induction of water and ethanol (4% w/v in water) self-administration, after 4 months, and after 12 months of 22-hour daily concurrent access to ethanol and water.

Results: Significant changes were observed in ACTH, cortisol, and 45/60 plasma proteins: a majority (28/45) were suppressed as a function of ethanol self-administration, 8 proteins were elevated, and 9 showed biphasic changes. Cortisol and ACTH were greatest during induction, and correlations between these hormones and plasma proteins varied across the experiment. Pathway analyses implicated nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) as possible mediators of ethanol-induced effects on immune-related proteins in primates.

Conclusions: Chronic ethanol consumption in primates leads to an allostatic state of physiological compromise with respect to circulating immune- and stress-related proteins in NF-κB- and STAT/JAK-related pathways in correlation with altered endocrine activity.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Mean (± SEM) levels of 28 circulating proteins (14 shown here) were suppressed after 4 or 12 months of ethanol self-administration in cynomolgus monkeys (N = 10) relative to baseline or induction of drinking. The four similar symbols represent experimental phases in chronological order, left to right: baseline, induction (cumulative intake, 9.3 g/kg), 4 and 12 months of ethanol self-administration. See Figure S2 for post-hoc comparisons.
Figure 2
Figure 2
Mean (± SEM) levels of 28 circulating proteins (14 shown here) were suppressed after 4 or 12 months of ethanol self-administration in cynomolgus monkeys (N = 10) relative to baseline or induction of drinking. The four similar symbols represent experimental phases in chronological order, left to right: baseline, induction (cumulative intake, 9.3 g/kg), 4 and 12 months of ethanol self-administration. See Figure S3 for post-hoc comparisons.
Figure 3
Figure 3
Mean (± SEM) levels of eight circulating proteins were increased after 4 or 12 months of ethanol self-administration in cynomolgus monkeys (N = 10) relative to baseline or induction of drinking. The four similar symbols represent experimental phases in chronological order, left to right: baseline, induction (cumulative intake, 9.3 g/kg), 4 and 12 months of ethanol self-administration. See Figure S4 for post-hoc comparisons.
Figure 4
Figure 4
Mean (± SEM) levels of nine circulating proteins both increased and decreased across the experimental phases in cynomolgus monkeys (N = 10). The four similar symbols represent experimental phases in chronological order, left to right: baseline, induction (cumulative intake, 9.3 g/kg), 4 and 12 months of ethanol self-administration. See Figure S5 for post-hoc comparisons.
Figure 5
Figure 5
Results of a network analysis based on transcription factor relationships (dashed, inhibitory; solid, positive; dotted, unknown) revealed nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) as a central transcriptional hub. Apo, apolipoprotein; A2M, α2-macroglobulin; CCL, chemokine (C-C motif) ligand; comp 3, complement 3; CRP, C-reactive protein; CXCL5, epithelial cell-derived neutrophil-activating peptide-78; F3, tissue factor; Ig, immunoglobulin; IL, interleukin; MMP, matrix metalloproteinase; PAX, paired box gene; SAP, serum amyloid protein; SERPINE, plasminogen activation inhibitor; TNFR, tumor necrosis factor receptor; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor.
Figure 6
Figure 6
Results of a network analysis based on transcription factor relationships (dashed, inhibitory; solid, positive; dotted, unknown) revealed JAK/STAT as transcriptional hubs. A2M, α2-macroglobulin; AR, androgen receptor; CCL, chemokine (C-C motif) ligand; CRP, C-reactive protein; F3, tissue factor; FABP, fatty acid binding protein; fib, fibrinogen; IFN, interferon; IL, interleukin; Ig, immunoglobulin; IGF, insulin-like growth factor; JAK, janus kinase; KLK3, prostate-specific antigen, free; MMP, matrix metalloproteinase; SERPINE, plasminogen activation inhibitor; STAT, signal transducer and activator of transcription; VEGF, vascular endothelial growth factor.
Figure 7
Figure 7
ACTH and cortisol from samples obtained at 12:00 p.m. and assayed for 60 plasma proteins during baseline (BL), induction (IND) and after 12 months of concurrent access to ethanol and water (12MO).
See this image and copyright information in PMC

References

    1. Achur RN, Freeman WM, Vrana KE. Circulating cytokines as biomarkers of alcohol abuse and alcoholism. J Neuroimmune Pharmacol. 2010;5:83–91. - PMC - PubMed
    1. Adinoff B, Marin PR, Bone GHA, Eckardt MJ, Roehrich L, George DT, Moss HB, Eskay R, Linnoila M, Gold PW. Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotrophin releasing hormone and corticotrophin levels in alcoholics after recent and long-term abstinence. Arch Gen Psychiatry. 1990;47:325–330. - PubMed
    1. Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcohol Clin Exp Res. 2003;27:1420–1427. - PubMed
    1. Banks WA, Erickson MA. The blood-brain barrier and immune function and dysfunction. Neurobiol Dis. 2010;37:26–32. - PubMed
    1. Bebo BF, Linthicum DS. Expression of mRNA for 55-kDa and 75-kDa tumor necrosis factor (TNF) receptors in mouse cerebrovascular endothelium: effects interleukin-1 beta, interferon-gamma and TNF-alpha on cultured cells. J Neuroimmunol. 1995;62:161–167. - PubMed

Publication types

MeSH terms