Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 676-687 © Pleiades Publishing, Ltd., 2026.

676

REVIEW

The Roles of Corticosterone, Interleukin-1β,

and Their Interactions in the Development

of Stress-Induced Anxiety-Like Behavior

in Laboratory Rodents

Anisa I. Vysotskaya

and Galina T. Shishkina

1,a

Federal Research Center Institute of Cytology and Genetics,

Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

e-mail: gtshi@bionet.nsc.ru

Received January 21, 2026

Revised May 12, 2026

Accepted May 13, 2026

Abstract— Psychoemotional disorders such as depression and anxiety are associated with adverse life ex-

periences, but the precise mechanisms underlying the induction of psychopathologies, particularly anxiety,

remain unclear. Among the wide range of biological alterations triggered by stressors, two systems – the

hypothalamic–pituitary–adrenocortical (HPA) axis and the immune system – have been most extensively

studied. Activation of the HPA axis leads to a rapid increase in glucocorticoids (cortisol in humans and

corticosterone in rodents), which play a central role in coordinating adaptive stress responses. However,

this increase can also lead to the development of psychopathologies. Elevated levels of peripheral and cen-

tral proinflammatory cytokines have been reported in both patients with anxiety symptoms and laboratory

animals. Elucidating the contribution of immune and glucocorticoid responses to stress-related behavioral

outcomes is complicated by complex and bidirectional interactions between these systems. While corticos-

terone, consistent with the well-established immunosuppressive activity of glucocorticoids, can exert anti-in-

flammatory effects, elevated levels of this hormone may also promote systemic inflammation by enhancing

the production of proinflammatory cytokines. Conversely, cytokines can modulate HPA axis activity, further

influencing stress responses. The review summarizes experimental evidence on the roles of glucocorticoid

hormones and the key proinflammatory cytokine interleukin-1β (IL-1β), as well as their interactions, in the

development of stress-induced anxiety. A better understanding of these mechanisms may help clarify the

pathophysiology of anxiety disorders.

DOI: 10.1134/S0006297926600201

Keywords: stress, anxiety, corticosterone, interleukin-1β, brain

* To whom correspondence should be addressed.

INTRODUCTION

Stressful events are major contributors to men-

tal health disorders such as anxiety and depression,

both of which profoundly affect social functioning

and overall quality of life [1-3]. However, the search

for effective strategies to prevent and/or mitigate

stress-induced psychopathologies, particularly anxi-

ety, is hindered by a lack of understanding of mech-

anisms underlying their onset and development.

Experimental studies in animal models have revealed

numerous biochemical and morphological changes in

the body following exposure to stressors, including

imbalance of neurotransmitters in the brain, endo-

crine dysregulation, inflammatory and neurodegen-

erative processes [4, 5], and altered expression of

regulatory microRNAs [6]. Among biological systems

implicated in the stress response, the hypothalamic–

pituitary–adrenocortical (HPA) axis and the immune

system have received the greatest attention.

The principal components of the HPA axis are

the hypothalamus, the anterior pituitary gland, and

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

the adrenal cortex. In response to stress, the hy-

pothalamus secretes corticotropin-releasing factor

(CRF), which stimulates the production of adreno-

corticotropic hormone (ACTH) in the pituitary. ACTH

activates the synthesis of glucocorticoids (cortisol in

humans and corticosterone in rodents) by the adre-

nal glands  [7]. Rapid activation of the HPA axis ini-

tiates mobilization of body’s protective and adaptive

resources required for survival under adverse condi-

tions  [8]. According to the Selye’s concept of general

adaptation syndrome, the organism is capable of suc-

cessfully coping with repeated stress exposure over

prolonged periods of time  [9]. However, excessive

activation of HPA and elevated corticosteroid levels

can contribute to the development of psychopathol-

ogies, including anxiety, partly through metabolic

and neurodegenerative mechanisms. Consequently,

anti-glucocorticoid therapy has been proposed as

potential treatment for certain mental diseases  [10].

The mechanisms of action of some anxiolytic agents

are associated with modulation of the HPA axis  [11].

The effects of glucocorticoids are mediated by two

classes of receptors: glucocorticoid receptors (GRs)

and mineralocorticoid receptors (MRs), which func-

tion as ligand-activated transcription factors. GRs,

which have a lower affinity for glucocorticoids  [12],

are particularly important under stress conditions;

for example, GRs prevent excessive elevation of gluco-

corticoid concentrations through a negative feedback

mechanism  [13].

Another major factor contributing to psychoemo-

tional disorders, including depression  [14-17] and

anxiety  [18], is stress-induced alterations in immune

function. In rodent studies, systemic administration

of proinflammatory cytokines, e.g., interleukin-1β

(IL-1β)  [19], or bacterial endotoxins, such as lipopoly-

saccharide (LPS)  [20,  21], induced behavioral changes

similar to those caused by stress exposure or gluco-

corticoid administration. Elevated levels of proinflam-

matory cytokines have been observed in laboratory

animals exhibiting anxiety-like behavior following

stress exposure  [22,  23], as well as in some patients

with symptoms of generalized anxiety disorder  [24].

However, the contribution of glucocorticoids and cy-

tokines to anxiety remains unclear, largely due to still

poorly understood interactions between them [25].

For example, in line with the well-established immu-

nosuppressive effects of glucocorticoids, corticoste-

rone can produce the anti-inflammatory effect, while

elevated levels of this hormone may promote systemic

inflammation by enhancing the production of proin-

flammatory cytokines  [26]. In turn, proinflammatory

agents can stimulate activity of the HPA axis  [27].

Early studies demonstrated that peripheral or cen-

tral administration of LPS to mice increased circulat-

ing levels of ACTH and corticosterone and promoted

anxiety-like behavior  [28]. Peripheral or central ad-

ministration of IL-1β also elevated corticosterone lev-

els in blood plasma  [19].

Currently, a large body of evidence has been

accumulated regarding the role of glucocorticoids

and proinflammatory cytokines in the formation of

stress-induced depression and, to a lesser extent, anx-

iety. However, the question of their combined contri-

bution has only recently begun to attract attention.

It was suggested that “detecting the immune mech-

anism of stress-linked psychiatric disorders, such as

anxiety disorders, can provide a novel insight into

comprehensively understanding the pathophysiology

of anxiety disorders”  [29]. In this review, we analyzed

experimental data on the role of corticosterone and

the key proinflammatory cytokine IL-1β, as well as

their interactions, in the development of stress-in-

duced anxiety. Understanding these mechanisms

may facilitate the development of novel therapeutic

strategies targeting glucocorticoids levels and IL-1β

signaling pathways.

MODELING INCREASED

ANXIETY IN RODENTS

Increased anxiety is defined as a fear of certain

situations that do not present an immediate danger

but are perceived as potentially dangerous[30]. To in-

vestigate the neurobiological mechanisms of stress-in-

duced anxiety, researchers commonly employ animal

models, particularly rodents. Among these, the chron-

ic unpredictable stress (CUS) paradigm based on daily

exposure to varying stressors, is considered one of

the most relevant models for reproducing psychoemo-

tional responses to real-life stress, including height-

ened anxiety. Numerous studies have demonstrated

the anxiogenic effects of CUS exposure [31-35]. How-

ever, CUS does not consistently induce increased anx-

iety-like behavior in animals [36, 37], which may be

due to differences in the duration and intensity of

stress exposure, genetic background, and other fac-

tors. For example, CUS failed to increase anxiety-like

behavior in C57BL/6 mice after 4 weeks of exposure,

whereas a significant anxiogenic effect was observed

after 8 weeks [33]. The lack of increase in anxiety

in female Sprague–Dawley rats subjected to mild CUS

for 6weeks was attributed to a relatively low intensi-

ty of stress procedures, which may have allowed the

animals to adapt to stressors [38].

Chronic exposure to both heterotypic and homo-

typic stressors can lead to increased anxiety levels.

Commonly used homotypic stressors include social

defeat [39, 40], restraint [41-44], and exposure to

a predator (e.g., ferret) or predator odor [45]. The

social defeat paradigm models psychological stress

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

induced by aggressive interactions, typically involv-

ing attacks by a resident animal toward an intruder,

which subsequently develops submissive behavior.

Existing methods of restraint in rodents vary in the

degree and duration of movement restriction and,

therefore, in the intensity of elicited stress response.

Classic immobilization involves complete restriction

of movement, for example by securing all four limbs

to a board with adhesive tape  [46]. Although this pro-

cedure induces one of the strongest stress responses,

it is now used less frequently than milder restraint

methods  [47]. More commonly, animals are subjected

to restraint procedures that limit, but do not entirely

prevent, movement, such as confinement in a narrow

plastic or wire container. In some protocols, the effect

of stress is further enhanced by additionally fixing the

animal’s limbs within the restraint device  [41]. Immo-

bilization is generally considered to produce stron-

ger activation of the HPA axis than restraint alone.

Naturalistic, non-invasive stressors such as predators

(e.g., ferrets) or their odors can also activate the HPA

axis  [48,  49] and increase anxiety-like behavior  [50].

In rodent studies, predator-related stress is commonly

induced using predator odors (e.g., cat urine) or syn-

thetic thiazoline derivatives.

Anxiety-like behavior in laboratory rodents is

commonly evaluated using behavioral paradigms that

exploit rodents’ innate aversion to potentially dan-

gerous open and brightly illuminated environments.

The most widely used assays include the elevated

plus maze (EPM) test [40, 51-53], the light–dark box

test [54], and the open field test. The EPM consists of

two open arms and two enclosed arms elevated above

the floor. Anxiety-like behavior is evaluated based on

the number of entries into the open arms and the

amount of time spent there. In the light–dark box

test, anxiety is assessed by measuring the time spent

in the illuminated compartment and the frequency of

transitions between the light and dark compartments.

The open field test is primarily designed to evaluate

the locomotor activity. Anxiety levels are estimated

from the amount of time spent in the central versus

peripheral zones of the test field  [55]. Other frequent-

ly used indicators of anxiety levels across these par-

adigms are the number of fecal boluses and episodes

of urination.

CORTICOSTERONE IN STRESS-INDUCED

INCREASES IN ANXIETY LEVELS

Elevated corticosterone levels and increased

anxiety-like behavior are commonly observed fol-

lowing exposure to various stressors. For instance,

CUS administered for 28 days in male mice resulted

in heightened anxiety-like behavior in the EPM test,

accompanied by increased corticosterone levels in

blood plasma  [56]. Comparable effects were reported

in male rats exposed to similar stress paradigms  [5].

Restraint of male Wistar rats for 2  h daily over 10

consecutive days using specialized rodent restraint

bags, elevated plasma corticosterone levels and en-

hanced anxiety-like behavior in the open field and

EPM tests [44]. In another model, six consecutive

days of social defeat stress in male mice increased

circulating corticosterone levels immediately after

stress exposure and elevated anxiety-like behavior in

the open field test on the following day[57]. The con-

tribution of stress-induced corticosterone elevation to

increasing symptoms of anxiety-like behavior is fur-

ther supported by findings showing that pharmaco-

logical blockade of corticosterone synthesis or GRs

attenuates these behavioral effects [52, 58].

However, chronic stress studies indicate that el-

evated anxiety-like behavior is not always associat-

ed with increased corticosterone levels. For example,

male rats subjected to 2  h of daily restraint in PVC

cones for 3  weeks displayed increased anxiety-like

behavior despite reduced, rather than elevated, cor-

ticosterone concentrations  [59]. These findings likely

reflect adaptation or dysregulation of the HPA axis

after repeated stress exposure. Consistent with this

interpretation, mice of both sexes exposed to vari-

able stressors for 6  weeks exhibited anxiety-like phe-

notypes in the EPM test together with reduced HPA

axis responsiveness to acute stressor challenge [60].

The lack of association between peak corticosterone

concentrations and anxiety levels is also indicated by

the attenuation of anxiety-like behavior symptoms

against a background of higher corticosterone levels

in the blood  [61].

The strongest association between anxiety-like

behavior and elevated plasma corticosterone is ob-

served in response to brief exposure to stressors.

Rats  [59] and mice  [42] subjected to 2 and 4  h of

restraint stress, respectively, demonstrated increase

in peripheral corticosterone levels accompanied by

heightened anxiety-like behavior. Notably, even initial

stress-induced elevation in corticosterone levels may

contribute to persistent long-term increase in anxi-

ety. For instance, a single corticosterone administra-

tion in rats was sufficient to increase anxiety-like be-

havior in the EPM test 12  days later  [62]. Additional

evidence for the role of stress-induced corticosterone

elevation in the initiation of anxiety comes from a

recent study by Belo-Silva et  al.  [37]. In mice housed

under standard conditions, unpredictable stress for

11  days attenuated both hormonal and behavioral re-

sponses to repeated stress exposure, as reflected by

normalized corticosterone levels and the absence of

increase in anxiety-like behavior. In contrast, stressed

mice maintained in enriched environments exhibited

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

significantly elevated anxiety despite relatively low

corticosterone levels; this effect was accompanied by

increased ACTH concentrations. The authors proposed

that direct ACTH action on the brain contributes to

the maintenance of anxiety-like behavior. Importantly,

blockade of corticosterone synthesis with metyrapone

before the initial stress exposure prevented the devel-

opment of anxiety in mice housed in enriched envi-

ronments. These findings suggest that acute stress-in-

duced elevations of corticosterone levels are critical

for the induction of anxiety-like behavior.

The mechanisms underlying the anxiogenic ef-

fects of chronic stress and glucocorticoids are not yet

fully understood. Proposed mechanisms include neu-

rodegenerative changes in key brain regions, partic-

ularly the hippocampus and the cerebral cortex, sup-

pression of hippocampal neurogenesis, and reduced

levels of neurotransmitters involved in emotional reg-

ulation, such as dopamine and serotonin [5]. Stress

is also associated with structural brain alterations,

including dendritic hypertrophy in the basolateral

amygdala, a change linked to heightened anxiety-like

behavior [62]. In addition, elevated anxiety has been

associated with oxidative stress, reduced expression

of brain-derived neurotrophic factor (BDNF) in the

hippocampus, and metabolic disturbances such as

increased levels of low-density lipoprotein (“bad”)

cholesterol [44, 63].

Beyond microglia, astrocytes are increasingly rec-

ognized as key participants in stress responses and

pathogenesis of anxiety disorders. Recent studies in

male mice demonstrated a critical role of astrocyt-

ic GRs in the ventral hippocampus in the regulation

of anxiety-like behavior [64]. Chronic restraint stress

in special tubes (2  h/day for 10  days) reduced GR ex-

pression in the ventral hippocampus, but not in the

dorsal hippocampus or amygdala. Chronic corticos-

terone administration induced anxiety-like behavior

and was accompanied by a marked reduction in GR

expression in the ventral hippocampus. Furthermore,

selective deletion of GRs in astrocytes was sufficient

to induce anxiety-like behavior in experimental ani-

mals.

Overall, these findings support the role of glu-

cocorticoids as major mediators of stress-induced

anxiety. However, the variability in long-term behav-

ioral and endocrine outcomes reported across stud-

ies suggests that additional factors are involved that

act either independently of or in interaction with

glucocorticoid signaling. Because exposure to stress-

ors is frequently accompanied not only by elevated

glucocorticoid levels but also by activation of the im-

mune system, increasing attention has been directed

toward the contribution of neuroimmune processes

to the development of stress-related psychiatric dis-

orders  [65].

STRESS-INDUCED CHANGES

IN INTERLEUKIN-1β EXPRESSION

ACCOMPANIED BY INCREASED ANXIETY

The interleukin-1 (IL-1) family includes approx-

imately 11 members, with IL-1β recognized as one

of the most potent proinflammatory cytokines. It is

predominantly produced by macrophages, microglia,

monocytes, and dendritic cells. Another important

contributor to stress-induced elevation in peripheral

proinflammatory cytokines is population of T  cells

(T  lymphocytes). For instance, repeated social defeat

stress over five days in adult male Sprague–Dawley

rats increased the number of mature T  cells immu-

noreactive for proinflammatory cytokines, elevated

serum levels of IL-1β and IL-6, and was associated

with enhanced anxiety-like behavior  [23]. Similarly,

unmedicated patients with anxiety disorders demon-

strated alterations in CD4+ T-cell subpopulations

(T  helpers). It was proposed that some of these im-

mune changes contribute to heightened anxiety un-

der chronic stress conditions  [29].

In most rodent studies, chronic stress exposure

leads to concomitant increases in proinflammato-

ry cytokines and glucocorticoids. For example, four

weeks of mild CUS increased anxiety-like behavior in

the EPM test in male Swiss mice, alongside elevated

serum corticosterone and increased levels of tumor

necrosis factor-alpha (TNF-α) and IL-6  [56]. Studies

in C57BL/6 mice revealed sex-dependent differences

in proinflammatory cytokine responses, which may

underlie sex-specific differences in psychoemotional

responses to stressors  [55]. It was found that male

mice restrained in plastic semicircular centrifuge

tubes for 2  h daily under bright light for four weeks

exhibited increased anxiety-like behavior in the open

field test, whereas chronically stressed females did

not differ from the controls. Although corticosterone

levels showed a trend toward elevation in both sexes,

males displayed a pronounced stress-induced increase

in circulating proinflammatory cytokines (IL-1β and

TNF-α) in parallel with heightened anxiety-like behav-

ior, whereas stressed females showed neither signifi-

cant cytokine elevation nor behavioral changes  [55].

In rodents, stress-induced elevations of IL-1β in

both peripheral circulation and brain have been con-

sistently associated with heightened anxiety-like be-

havior  [66,  67]. Administration of IL-1β, either periph-

erally (30, 100, 300, or 1000  ng) or centrally (20  ng),

produced anxiogenic effects in the EPM test and

increased plasma corticosterone levels  [68,  69]. Con-

versely, targeted suppression of IL-1β expression in

the hippocampus markedly attenuated anxiety- and

depressive-like behaviors induced by LPS administra-

tion  [70]. Central IL-1β administration elevated corti-

costerone levels and increased anxiety-like behavior

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

in the EPM test  [71]. The involvement of glucocorti-

coid signaling in these effects is supported by the fact

that pre-treatment with the GR antagonist mifepris-

tone reduced both behavioral and endocrine respons-

es to IL-1β.

Stress-induced anxiety is further linked to altered

regulation of local neuronal excitability in the hip-

pocampus, which serves as a principal link in the

control of emotions and responses to stressors by in-

teracting with other brain structures, including the

prefrontal cortex, amygdala, and hypothalamus [72,

73]. In C57BL/6 mice, single or repeated social defeat

stress increased expression of c-Fos (neuronal activa-

tion marker) in the prefrontal cortex, lateral septum,

bed nucleus of the stria terminalis, paraventricu-

lar nucleus of the hypothalamus, medial amygdala,

and hippocampus. These changes were accompanied

by microglial activation and elevated IL-1β expres-

sion [74]. The light–dark box test further confirmed

a significant increase in anxiety levels after repeat-

ed exposure. Similarly, in male Sprague–Dawley rats,

social defeat stress daily for 5 consecutive days in-

creased anxiety-like behavior in the EPM test without

affecting the locomotor activity, while also elevating

plasma IL-1β levels, inducing microglial activation in

the basolateral amygdala, and enhancing neuronal

activity in this region [23]. The functional link be-

tween IL-1β and amygdala hyperexcitability is sup-

ported by evidence that peripheral IL-1β administra-

tion increases spontaneous firing rates of neurons in

the amygdala [75].

However, published reports on stress-induced

changes in brain IL-1β levels are inconsistent, likely

reflecting differences in stressor modality, intensity,

and duration, as well as variability in animal sex and

genotype [76]. For instance, in Sprague–Dawley rats,

acute restraint stress (1-2  h) had no effect on IL-1β

expression in the hypothalamus, whereas Fischer344

rats were characterized by a more pronounced corti-

costerone response and exhibited significant increases

in both IL-1β mRNA and protein in this region [77].

A relatively moderate stressor, such as forced swim-

ming (25-30  min at 25°C), failed to produce last-

ing changes in IL-1β levels in the brain regions of

Sprague–Dawley rats, including the hypothalamus,

over subsequent 24  h  [78]. Single or repeated ex-

posure to a natural psychogenic stressor, such as a

predator (ferret), elicited a rapid fear response and

transient elevation of plasma corticosterone in male

Sprague–Dawley rats at 5  min but not 2  h post-expo-

sure, without detectable changes in IL-1β mRNA lev-

els in the studied regions (prefrontal cortex, amygda-

la, hippocampus, and hypothalamus)  [49].

In contrast, more severe stressors can induce re-

gion-specific alterations in IL-1β levels. Inescapable

electric shock produced a transient increase in hy-

pothalamic cytokine levels in male Sprague–Dawley

rats immediately and 4  h after exposure, but not at

8 or 24  h. No changes were observed in the hippo-

campus at any time point, whereas the prefrontal

cortex showed a delayed decrease at 4 and 8  h [79].

Similar results were observed following rigid immo-

bilization stress applied using the Kvetnansky and

Mikulaj protocol [46]: after 60 min, the content of

IL-1β mRNA increased in the hypothalamus but re-

mained unchanged in other brain regions, including

the cerebral cortex, hippocampus, striatum, thalamus,

midbrain, brainstem, and cerebellum [47]. Notably,

this upregulation of IL-1β expression in the hypo-

thalamus was temporary; the levels of IL-1β declined

after 60  min despite continued immobilization for up

to 240  min.

Stress-induced increases in IL-1β expression in

the central nervous system (CNS) can occur through

multiple pathways, including the transport of IL-1β

itself and the trafficking of peripheral immune cells

that produce this cytokine into the brain. Although

the blood–brain barrier is relatively impermeable to

circulating cytokines and immune cells, experimen-

tal evidence demonstrates that peripherally adminis-

tered, radiolabeled IL-1β can enter the mouse brain

[80]. Infiltration of IL-1β-producing monocytes into

the brain has been linked to heightened anxiety-like

behavior during chronic stress  [81,  82]. The involve-

ment of corticosterone in the regulation of monocyte

release from the bone marrow into the bloodstream

has been demonstrated in C57BL/6 mice using the

chronic social defeat stress model. Both adrenalecto-

my and pharmacological inhibition of glucocorticoid

synthesis using metyrapone attenuated stress-induced

release of monocytes without affecting their produc-

tion  [83]. Peripheral cytokines and peripheral im-

mune cells producing these compounds activate mi-

croglial cells, the resident immune cells of the brain,

which comprise up to approximately 12% of total

brain cells  [84]. Activated microglia amplify neuroin-

flammatory signaling by increasing the local produc-

tion of pro-inflammatory cytokines, including IL-1β,

in the CNS.

Overall, these findings indicate that chronic

stress, which is implicated in the emergence of psy-

choemotional disorders including anxiety, can ele-

vate both circulating IL-1β levels and the number of

IL-1β-producing monocytes. Stress-induced peripheral

immune alterations influence IL-1β expression and

neuronal activity in the brain. Peripheral inflamma-

tion exacerbates neuroinflammation through several

mechanisms, including disruption of the blood–brain

barrier, migration of immune cells, and activation of

microglia. However, it remains unclear whether im-

mune activation during stress exposure amplifies or

weakens accompanying psychoemotional responses.

CORTICOSTERONE AND INTERLEUKIN-1β IN ANXIETY DEVELOPMENT 681

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Scheme  1. Interactions between the HPA axis and IL-1β signaling in the development of stress-induced anxiety-like behavior.

Direct and feedback interactions are shown with solid and dashed arrows, respectively; the direction of parameter changes

is indicated by short arrows.

MOLECULAR MECHANISMS

OF THE GLUCOCORTICOID INFLUENCE

ON INTERLEUKIN-1β EXPRESSION

Comparison of temporal changes in peripher-

al glucocorticoid and cytokine levels in response

to stress exposure suggests that glucocorticoids are

released rapidly, which is believed to prevent the

damaging effects of potentially excessive immune

system activation through their anti-inflammatory ef-

fects  [15,  25]. However, evidence indicates that both

endogenous glucocorticoids and synthetic analogs

(e.g., dexamethasone) can either decrease or increase

proinflammatory cytokine production  [26, 85-87].

A key determinant of these effects appears to be the

timing of glucocorticoid exposure relative to the onset

of inflammation. For instance, corticosterone admin-

istration prior to LPS exposure significantly exacer-

bated LPS-induced neuroinflammation  [88]. Similarly,

stress exposure preceding LPS administration pro-

moted neuroinflammation and increased anxiety-like

behavior in BALB/c mice in the light–dark box test

[89]. Chronic exposure to glucocorticoids can modu-

late stress-induced expression of the IL-1β gene. For

example, prolonged corticosterone administration via

drinking water enhanced stress-induced IL-1β mRNA

expression in the hippocampus and cerebral cortex

in mice  [90].

Glucocorticoids suppress inflammation by inhib-

iting transcriptional activity and post-translational

regulation of proinflammatory genes  [91]. Thus, the

binding of GR to the negative glucocorticoid response

element (nGRE) in the promoter region of the human

IL1B gene represses its transcription  [92]. The proin-

flammatory action of glucocorticoids may involve up-

regulation of the FK506-binding protein 51 (FKBP51),

which suppresses the activity of GRs and facilitates

activation of proinflammatory cascades, ultimately

contributing to enhanced neuroinflammation [87].

The fact that glucocorticoids can differentially reg-

ulate IL-1β depending on concentration and recep-

tor engagement was demonstrated in BV2 microglial

VYSOTSKAYA, SHISHKINA682

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

cells: high-dose corticosterone (500  nM) suppressed

LPS-induced IL-1β production via GR activation,

whereas low-dose corticosterone (50  nM) enhanced

NF-κB translocation to the nucleus via MR signaling,

leading to increased IL-1β expression  [93]. Together,

these findings suggest that IL-1β serves as a key me-

diator linking neuroendocrine stress responses with

behavioral outcomes. Elucidating this bidirectional

regulation will contribute to understanding the mech-

anisms of individual resilience and vulnerability to

stress-induced psychopathologies.

CONCLUSION

Exposure to stress activates the HPA axis and

the immune system, and both systems are involved

in the formation of anxiety-like behavior in response

to stress. Discrepancies in behavioral outcomes re-

ported across studies may reflect context-dependent

and bidirectional interactions between these systems

at peripheral and central levels. The proinflamma-

tory cytokine IL-1β appears to serve as a mediator

between stress-induced neuroendocrine changes and

behavioral responses. Its expression is dynamically

regulated by glucocorticoids, particularly corticoste-

rone, as well as by expression and sensitivity of GRs,

leading to either upregulation or suppression.

The interaction between glucocorticoid signaling

and immune system in promoting stress-induced anx-

iety-like behavior is illustrated in Scheme  1. Elevated

corticosterone levels increase circulating proinflam-

matory monocytes and facilitate their penetration into

the brain. Once within the CNS, these cells contribute

to the activation of microglia and enhanced produc-

tion of IL-1β. This neuroimmune cascade is associated

with heightened anxiety-like behavior manifested as

reduced time and fewer entries into the open arms

of the EPM, decreased time spent and distance trav-

eled in the central zone of the open field test, and

reduced time spent in the light compartment of the

light–dark box.

Abbreviations

ACTH adrenocorticotropic hormone

EPM elevated plus maze

FKBP51 FK506-binding protein 51

GR glucocorticoid receptor

HPA hypothalamic–pituitary–adrenal

IL-1β interleukin-1β

LPS lipopolysaccharide

MR mineralocorticoid receptor

TNF-α tumor necrosis factor-alpha

Contributions

G.T.S. developed the study concept and wrote the text

of the article; A.I.V. and G.T.S. collected published data

and edited the manuscript.

Funding

This work was supported by the State Assignment

to the Institute of Cytology and Genetics, Siberian

Branch of the Russian Academy of Sciences (FWNR-

2022-0023).

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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