TNF-α gene upregulation and cytokine changes in mice under chronic unpredictable stress
Department of Biology, College of Education for Pure Sciences, University of Kirkuk, Kirkuk, Iraq.
Research Article
Open Access Research Journal of Life Sciences, 2026, 11(02), 029-039.
Article DOI: 10.53022/oarjls.2026.11.2.0017
Publication history:
Received on 03 March 2026; revised on 03 April 2026; accepted on 07 April 2026
Abstract:
Background: Psychological stress is a major contributing factor to psychiatric and immune system disorders. While tumour necrosis factor-alpha (TNF-α) is recognised as a key inflammatory mediator, its precise gene expression alterations under chronic stress remain incompletely understood. This study aimed to investigate the impact of chronic unpredictable stress (CUS) on anxiety- and depression-like behaviours, hypothalamic-pituitary-adrenal (HPA) axis activity, and systemic inflammation, with a specific focus on TNF-α gene expression in mice.
Methods: Forty male albino mice were randomly divided into a control group and an experimental group subjected to a four-week CUS protocol. Behavioural alterations were assessed using the Elevated Plus Maze (EPM), Forced Swim Test (FST), and Tail Suspension Test (TST). Serum concentrations of HPA axis hormones (ACTH and CRF) and inflammatory cytokines (TNF-α, IL-6, and IL-17) were quantified. Additionally, TNF-α mRNA expression was analysed using RT-qPCR.
Results: CUS induced significant behavioural deficits, evidenced by reduced open-arm exploration in the EPM and increased immobility in the FST and TST (p<0.05), indicating exacerbated anxiety- and depression-like states. These behavioural changes were accompanied by HPA axis hyperactivation, marked by a significant increase in serum ACTH and CRF concentrations. Furthermore, CUS triggered a robust systemic inflammatory response, showing significantly elevated levels of TNF-α, IL-6, and IL-17. Crucially, RT-qPCR analysis revealed a significant upregulation of TNF-α gene expression in the CUS group, with an average fold change of 3.22-fold compared to 1.44-fold in the control group.
Conclusion: Chronic unpredictable stress effectively drives anxiety- and depression-like behaviours in mice by hyperactivating the HPA axis and upregulating pro-inflammatory networks. The significant overexpression of the TNF-α gene underscores its pivotal role in stress-induced systemic inflammation, offering potential molecular insights into the neuroendocrine-immune axis.
Keywords:
Chronic unpredictable stress; HPA axis; Neuroinflammation; Pro-inflammatory cytokines; Behavioral despair; Gene expression.
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