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P HYSIOLOGICAL R EVIEWS

Vol. 79, No. 1, January 1999

Printed in U.S.A.

Regulation of the Hypothalamic-Pituitary-Adrenal Axis by

Cytokines: Actions and Mechanisms of Action

ANDREW V. TURNBULL AND CATHERINE L. RIVIER

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California; and North

Western Injury Research Centre, University of Manchester, Manchester, United Kingdom

I. Introduction

A. Hormones and cytokines: deﬁnitions

B. Concept of bidirectional communication between immune and neuroendocrine systems:

a historical perspective

C. Cytokines

D. Hypothalamic-pituitary-adrenal axis

II. Cytokine Inﬂuence on Hypothalamic-Pituitary-Adrenal Axis Secretory Activity In Vivo

A. Animal studies

B. Human studies

III. Physiological/Pathophysiological Circumstances in Which Endogenous Cytokines Play a Role in

Regulation of Hypothalamic-Pituitary-Adrenal Axis

A. Viral disease

B. Endotoxin treatment

C. Local inﬂammation

D. Physical and psychological stress

E. Basal hypothalamic-pituitary-adrenal activity

IV. Cytokine Actions on the Central Nervous System, Pituitary, and Adrenal

A. Evidence that cytokines activate the hypothalamic-pituitary-adrenal axis primarily at the level of the

central nervous system

B. Evidence for direct effects of cytokines on pituitary adrenocorticotropic hormone secretion

C. Evidence for direct actions of cytokines on adrenal glucocorticoid secretion

V. Mechanisms of Hypothalamic-Pituitary-Adrenal Axis Activation by Interleukin-1

A. Direct actions on pituitary and adrenal

B. Penetration of cytokines into brain

C. Role of readily diffusible intermediates

D. Induction of intermediates at blood-brain barrier interface

E. Actions at circumventricular organs

F. Potential role of catecholamines and evidence of activation of medullary cell groups

G. Activation of vagal afferent ﬁbers

H. Cytokine synthesis within brain

I. Local interleukin-1 induction of circulating interleukin-6

VI. Conclusions

Turnbull, Andrew V., and Catherine L. Rivier. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cyto-

kines: Actions and Mechanisms of Action. Physiol. Rev. 79: 1 – 71, 1999. — Glucocorticoids are hormone products

of the adrenal gland, which have long been recognized to have a profound impact on immunologic processes. The

communication between immune and neuroendocrine systems is, however, bidirectional. The endocrine and immune

systems share a common ‘‘chemical language,’’ with both systems possessing ligands and receptors of ‘‘classical’’

hormones and immunoregulatory mediators. Studies in the early to mid 1980s demonstrated that monocyte-derived

or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis,

establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication

between the immune and neuroendocrine systems. The subsequent 10 – 15 years have witnessed demonstrations

that numerous members of several cytokine families increase the secretory activity of the HPA axis. Because this

neuroendocrine action of cytokines is mediated primarily at the level of the central nervous system, studies investi-

gating the mechanisms of HPA activation produced by cytokines take on a more broad signiﬁcance, with ﬁndings

relevant to the more fundamental question of how cytokines signal the brain. This article reviews published ﬁndings

that have documented which cytokines have been shown to inﬂuence hormone secretion from the HPA axis,

0031-9333/99 $15.00 Copyright

1999 the American Physiological Society

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ANDREW V. TURNBULL AND CATHERINE L. RIVIER

Volume 79

determined under what physiological/pathophysiological circumstances endogenous cytokines regulate HPA axis

activity, established the possible sites of cytokine action on HPA axis hormone secretion, and identiﬁed the potential

neuroanatomic and pharmacological mechanisms by which cytokines signal the neuroendocrine hypothalamus.

I. INTRODUCTION

kines. It certainly reﬂects best the deﬁnition that would

have been applied at the time when the majority of the

work described in this article was performed. Under any

A. Hormones and Cytokines: Deﬁnitions

deﬁnition, the term cytokine encompasses the ‘‘mono-

kines’’ (monocyte/macrophage-derived mediators) and

‘‘lymphokines’’ (lymphocyte-derived mediators), which

Deﬁning what is meant by the term hormone , and

were terms commonly used in the earlier studies de-

what is meant by the term cytokine , is certainly no easy

scribed in this review.

task. Indeed, the work reviewed in this article has changed

Table 1 was compiled of what is presently known of

many people’s opinion as to what our deﬁnitions of these

the features of hormones and cytokines. Although this is

classes of cell-cell signaling molecules should be. How-

again not deﬁnitive, it is fair to say that if the majority of

ever, we are faced at the outset with conveying to the

characteristics of the substance under consideration ﬁt in

reader what ‘‘we’’ mean when we use the terms cytokines

the cytokine column, then the substance is a cytokine,

and hormones throughout this review.

and if the majority of characteristics ﬁt in the hormone

A classical endocrinology textbook deﬁnition of a

column, then it is a hormone. It should be pointed out

hormone is ‘‘a biomolecule, which is produced by a spe-

that the same chemical substance could be classiﬁed dif-

cialized cell type, is secreted from a ductless gland di-

ferently depending on the ‘‘setting’’ under consideration.

rectly into the bloodstream, and acts on distant target

For example, prolactin produced by the pituitary and act-

cells/tissues, to regulate pre-existing cellular activities.’’

ing on the mammary gland is clearly acting in an ‘‘endo-

Chemically, hormones are small to large polypeptides,

crine hormone’’ fashion. However, prolactin can also be

proteins, glycoproteins, derivatives of aromatic amino

produced by, and act on, lymphocytes, a situation in

acids, or steroids. In the case of the pituitary peptide

which it might be better classiﬁed as a cytokine. Perhaps

hormone adrenocorticotropin (ACTH), it is produced by

the key difference between cytokines and hormones that

corticotropes (specialized cell type) within the anterior

we indicate in Table 1 is that cytokines are regulators of

pituitary (a ductless gland), is secreted into the general

predominantly local tissue processes, whereas hormones

circulation, and acts predominantly on the adrenal cortex

function as regulators predominantly of ‘‘systemic’’ or

(a distant target) to enhance glucocorticoid secretion.

‘‘whole body’’ homeostasis.

This is perhaps a narrow view of a hormone, because

many ‘‘classical’’ hormones are also synthesized and act

within the brain and are produced and act locally within

B. Concept of Bidirectional Communication

the periphery. On the other hand, it is perhaps too broad,

Between Immune and Neuroendocrine Systems:

because under this deﬁnition CO 2 produced by exercising

a Historical Perspective

muscle and stimulating respiration might have to be con-

sidered a hormone also. However, it is a fairly accurate

description of what most people understand when think-

Regulation of the immune system by the adrenal

gland was observed as early as the middle of the 19th

ing of a hormone acting in a ‘‘classical endocrine fashion.’’

In contrast to hormones that have most commonly century when Thomas Addison (3) documented that a

patient with adrenal insufﬁciency had an excess of circu-

been associated with the ‘‘endocrine system,’’ cytokines

have been classically associated with the ‘‘immune sys- lating lymphocytes. In agreement with this observation,

removal of the adrenal gland of the rat was found to pro-

tem.’’ Deﬁning a cytokine is even more difﬁcult than de-

ﬁning a hormone. For the purposes of the work described duce hypertrophy of the thymus (an organ responsible for

the manufacture of mature lymphocytes) (363). Perhaps

within this review, we found the deﬁnition used in The

Cytokine Handbook (862) most useful. Here cytokines are the best known of early experimental studies were those

of Hans Selye (764, 765), who found that enlargement

deﬁned as ‘‘regulatory proteins secreted by white blood

cells and a variety of other cells in the body; the pleiotro- of the adrenal gland and involution of the thymus were

communal features of an animal’s response to stress, re-

pic actions of cytokines include numerous effects on cells

of the immune system and modulation of inﬂammatory gardless of the nature of the injurious insult. These early

studies clearly suggested a close association between ad-

responses.’’ This deﬁnition is somewhat narrow in that it

probably overemphasizes the importance of the immune renal gland physiology and immune activity.

The isolation of the active principal of the adrenal

system as a source and target, but probably reﬂects most

accurately people’s ﬁrst thoughts when they think of cyto- cortex, cortisone, by Kendall and Reichstein in the late

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REGULATION OF HPA AXIS BY CYTOKINES

TABLE 1. Features of cytokines and classical endocrine hormones

Cytokine

Classical Endocrine Hormone

Structure

Large polypeptides, proteins, or

Small to large polypeptides, proteins, glycoproteins, derivatives of

glycoproteins

aromatic amino acids, or steroids

Cell sources

Secreted by white blood cells (and many

Secreted by one type of specialized cell within a ductless gland

other cells in numerous types of tissues

(an ‘‘endocrine gland’’)

and organs)

Concentrations in healthy,

Very low (virtually absent); increase

Usually measurable and commonly display pulsatile and circadian

stress-free subjects

markedly during tissue disease, injury, or

patterns of secretion

repair

Location of action relative

Act predominantly locally, in a paracrine or

Act on distant target cells

to secretion

autocrine manner

Range of activities

‘‘Pleiotropic,’’ multiple target cell types and

Breadth of actions highly variable: many anterior pituitary

broad spectrum of actions

hormones (e.g., TSH, ACTH) have highly limited actions, but

‘‘target gland’’ hormones (e.g., T 3 ,T 4 , and glucocorticoids) have

very broad range of activities

‘‘Redundancy’’

Display great overlap of biological activities

Far less overlap of biological activities; deﬁciency in single

(i.e., ‘‘redundancy’’)

hormone usually produces marked abnormalities

Function

Function predominantly as regulators of

Function predominantly as regulators of systemic or ‘‘whole

local tissue processes

body’’ homeostasis

TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropin; T 3 , 3,3 * ,5-triiodothyronine; T 4 , thyroxine.

inﬂammation (335), gave support to the hypothesis that

adrenal glucocorticoid (GC) secretion plays a signiﬁcant characterized by elevated plasma levels of GC (corticoste-

rone) (73). Furthermore, mice injected with supernatants

role in regulating immunologic processes. However, even

though marked elevations in the plasma blood concentra- from concanavalin A-stimulated peripheral blood or

spleen cells produce one or more GC-increasing factors

tion of GC are observed after all types of stressful stimuli,

studies showing that GC produce immunosuppression (GIF) that increase the blood concentrations of cortico-

sterone (68). These studies therefore suggested the exis-

were assumed (by the majority of workers) to be of phar-

macological, rather than of physiological, signiﬁcance. tence of an immune-neuroendocrine regulatory feedback

mechanism in which immune cells limited their own activ-

These ﬁndings advented the widespread use of GC-based

therapies for autoimmune and inﬂammatory disease. It ity by secreting molecules that stimulate the secretion of

adrenal GC.

was not until the late 1970s and the pioneering work of

Besedovsky, del Rey, Sorkin, and colleagues that a physio-

The concept of ‘‘bidirectional communication’’ be-

tween immune and endocrine systems became ﬁrmly es-

logical role for GC in preventing overactivity, and preserv-

ing the speciﬁcity, of immune reactions became estab- tablished with the seminal works of Edwin Blalock and

co-workers in the early 1980s. These workers began to

lished (67, 191). In a signiﬁcant review article of the early

1980s, Munck et al. (567) reinforced this concept. These describe molecular basis for such bidirectional communi-

cation (reviewed in Refs. 80 – 82, 952, 953). Their early

authors proposed the now commonly held view that en-

dogenous GC act to prevent ‘‘overshoot’’ of immune/in- studies showed a commonality in the pathways of action

of immunoregulators (e.g., interferon) and hormones

ﬂammatory responses, thus limiting the host defense re-

sponse to ﬁghting the aggressor (e.g., invading pathogen) (e.g., norepinephrine) (84). This group went on to dis-

cover that a number of classical hormones are not only

without the deleterious effects to the host of a hyperactive

immune system (e.g., autoimmunity). More recent work secreted by classical endocrine glands (e.g., pituitary) but

are also made by cells of the immune system (e.g., lym-

has indicated that the inﬂuence of GC on immunologic

processes is more complex than a generalized suppres- phocytes). For example, they showed that lymphocytes

synthesize ACTH, the pituitary hormone which is the ma-

sion of immune activity and depends on the type of im-

mune activity and the subset of immunologic cells in- jor physiological regulator of adrenal GC secretion (792).

In addition, they demonstrated that not only do lympho-

volved (see Ref. 531 for extensive review). However, it is

clear that endogenous GC are key regulators of immune cytes produce hormones such as ACTH, endorphins, thy-

rotropin, and growth hormone (792, 794, 951) but that

system function.

Further work by Besedovsky et al. (73) suggested these hormones were able to inﬂuence immunologic pro-

cesses (79, 83, 370, 371). Subsequent studies have demon-

that not only do GC have a profound impact on immune

activity, but that the converse is also true and immune strated that a number of hormones (e.g., prolactin, insulin-

like growth factor) are produced by lymphocytes (372,

activity inﬂuences GC secretion. This hypothesis grew out

of experimental observations that during the development 556, 557, 621).

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1940s, and the demonstration of its ability to suppress of an immune response to a foreign antigen (sheep red

blood cells), rats mount a parallel endocrine response

ANDREW V. TURNBULL AND CATHERINE L. RIVIER

Volume 79

an ACTH-like molecule, combined with the demonstration

that mice whose pituitary gland had been removed (hy- demonstrated a direct action of IL-1 on ACTH secretion

from primary cell cultures of rat anterior pituitary cells,

The ﬁnding that lymphocytes are able to synthesize resulted in articles being published back to back in a 1987

issue of Science (55, 62, 730). One of these studies (62)

pophysectomy) still produced a corticosterone response

to infection with the Newcastle disease virus (NDV), led thus supporting the earlier studies by Blalock and co-

workers (966) suggesting a direct action of IL-1 on the

Blalock and co-workers (793) to propose the concept of

lymphoid-adrenal axis. According to this hypothesis, pituitary gland to secrete ACTH. Conversely, the other

two Science papers (55, 730) found that IL-1 does not

ACTH produced by virus-stimulated lymphocytes acts on

the adrenal to increase corticosterone secretion. How- stimulate ACTH secretion from anterior pituitary cells in

primary culture, despite the fact that IL-1 in vivo elevates

ever, subsequent studies have failed to replicate the per-

sistance of an NDV-induced corticosterone response in plasma ACTH and GC concentrations. These latter two

groups (55, 730) showed that IL-1-induced ACTH secre-

hypophysectomized mice (64, 218, 221, 604), and the hy-

pothesis of a lymphoid-adrenal axis involving lymphoid tion in vivo is dependent on the secretion and action of

the hypothalamic 41-amino acid peptide CRF, which is the

production of ACTH molecule has fallen out of favor.

Furthermore, Besedovsky et al. (71) showed that stimu- major hypothalamic ACTH secretagogue. These ﬁndings

clearly implicate the hypothalamus as the site at which

lated lymphocytes secrete GIF that increase plasma ACTH

and corticosterone levels in rats and that this corticoste- the HPA axis response to IL-1 is mediated and gave great

support to the idea that immunoregulators could inﬂuence

rone response was prevented by hypophysectomy. Given

that the electrical and neurochemical activities of the hy- the activity of the central nervous system (CNS).

Controversy over the likely primary site of IL-1 action

pothalamus are also altered during the course of an im-

mune response (69, 72), Besedovsky et al. (71) proposed (CNS, pituitary gland, or possibly adrenal glands) in stimu-

lating pituitary-adrenal secretion has continued for many

that the effects of such GIF on adrenal GC secretion were

probably mediated at the hypothalamic component of the years and is considered in detail in sections IV and V .

However, a large body of evidence has now accumulated

hypothalamic-pituitary-adrenal (HPA) axis, rather than on

the pituitary or adrenal glands directly.

that indicates that IL-1 and other cytokines can signal the

brain. In parallel with studies investigating the relation-

The chemical identity of putative ‘‘GIF’’ became ap-

parent with the recognition that classical endocrine hor- ship between the immune system and HPA axis, a large

number of studies indicated that fever caused by invading

mones are not the only class of mediators involved in

immune-endocrine communication. Indeed, in the mid pathogens occurs as a result of the elaboration from im-

mune cells of an ‘‘endogenous pyrogen’’ capable of signal-

1980s, it became readily apparent that immunoregulatory

cytokines also form a key link between immune and neu- ing the CNS (reviewed in Refs. 23, 420). This endogenous

pyrogen was putatively identiﬁed as IL-1 (reviewed in Ref.

roendocrine systems (70, 331, 532, 966). Blalock and co-

workers (966) showed that the monokines interleukin 420). Furthermore, administration of IL-1 produces many

CNS-mediated changes including changes in behavior (re-

(IL)-1 and IL-6 (or hepatocyte-stimulating factor) stimu-

late ACTH secretion from the corticotropic tumor cell line duced exploration, reproductive activity, food-motivated

behavior, and increased sleep), changes in autonomic out-

AtT20. 1 A year later, Besedovsky et al. (70) demonstrated

that systemic administration of monocyte-derived or re- ﬂow, metabolic rate, and the activity of a number of neuro-

endocrine axes (see Refs. 54, 65, 408, 409, 439, 440, 529,

combinant IL-1 increases plasma ACTH and GC concen-

trations in normal mice. Furthermore, Besedovsky et al. 683, 708 for relevant reviews). Collectively, these studies

have provided strong evidence for the regulation by IL-1 of

(70) demonstrated that neutralization of endogenous IL-

1 inhibits the GC response to experimental viral infection CNS responses to peripheral changes in immune activity.

Furthermore, the common mediator of the effects on vari-

(NDV) in rats. This latter experiment clearly indicated

that the observations of stimulatory effects of cytokines ous CNS responses provides a molecular basis for the

observations of the stereotypical responses to immune

on neuroendocrine secretion were not merely pharmaco-

logical phenomena and suggested that IL-1 plays an im- challenges of diverse origins. This ‘‘acute phase response’’

to sickness is characterized by fever, appetite suppres-

portant endogenous role in regulating the HPA axis during

viral disease. Indeed, these landmark studies by Besedov- sion, anorexia, alterations in plasma cation concentra-

tions, synthesis of speciﬁc liver proteins (known as acute

sky and Blalock indicated that cytokines could be the

extrahypothalamic corticotropin-releasing factors (CRF) phase proteins), and changes in neuroendocrine secre-

tions (441). It is now ﬁrmly established that acute phase

released by injured tissue which had previously been re-

ported by Broddish and co-workers during the 1970s (112, responses are produced by the actions of, and complex

interactions between, IL-1 and numerous other cytokines.

113, 497).

Subsequent work by three independent laboratories

Since the landmark studies by the groups of Besedov-

sky and Blalock, it has become apparent that IL-1 has

1 Interleukin literally means ‘‘between leukocytes.’’

potent effects on the secretion of the majority of hor-

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REGULATION OF HPA AXIS BY CYTOKINES

TABLE 2. Inﬂuence of interleukin-1 on neuroendocrine

defense are now recognized. Accordingly, the expression

secretion

of these polypeptides and their receptors is not restricted

to cells of the immune system but is also found in many

Neuroendocrine System

Effect

Reference No.

other tissues (including the brain and endocrine glands).

Furthermore, many cytokines exert potent actions on a

Hypothalamic-pituitary-

Increases secretion

863, 883, 959

adrenal axis

variety of physiological activities outside of immunoregu-

Hypothalamic-pituitary-

Decreases secretion

683, 715, 882,

lation; for example, many cytokines induce fever, sleep,

gonadal axis

886

anorexia, malaise, and alterations in neuroendocrine se-

Hypothalamic-pituitary-

Decreases secretion

336, 358, 665,

thyroid axis

886

cretions. Finally, the ability of some cytokines to regulate

Somatotropic axis

Increases or decreases

634, 922

homeostatic processes at tissues distant from their site

secretion

of production has ﬁrmly established cytokines as key reg-

Prolactin secretion

Increases or decreases

671, 689

secretion

ulators of coordinated local and systemic responses to

Posterior pituitary

Increases secretion

158, 159, 446,

tissue trauma, infection, and disease.

hormone secretion

992

The classiﬁcation of cytokines into families has

Catecholamines

Increases secretion

54, 695

proven somewhat arbitrary. With the exception of a few

homologous peptides (e.g., IL-1 a and -1 b ; interferon- a

and - b ; and tumor necrosis factor- a ,- b ) most cytokines

mones under neuroendocrine control (see Table 2). Fur-

share little sequence similarity. Consequently, classiﬁca-

thermore, more recent studies have shown that alterations

tion of cytokines has been based on either functional attri-

in neuroendocrine secretion are produced not only by IL-

butes, target receptors, or cells of origin. Most commonly,

1, but also by many other immunoreglatory cytokines.

cytokines have been classiﬁed into families of interleu-

The HPA axis has remained the most extensively studied

kins, tumor necrosis factors (TNF), interferons (IFN),

neuroendocrine system with respect to the inﬂuence of

chemokines, hematopoietins (or neuropoietins), and col-

cytokines, and the ability to increase the secretory activity

ony-stimulating factors (CSF). Because of their similar

of this axis is a biological property of several interleukins,

actions particularly within the CNS and peripheral ner-

tumor necrosis factors, chemokines, hematopoietins, in-

vous system, growth factors (GF) and neurotrophins (NT)

terferons, growth factors, and neurotrophic factors.

have also been considered to fall under the umbrella term

This article reviews published ﬁndings that demon-

cytokine . Their overlapping actions lead to a number of

strate 1 ) which cytokines inﬂuence hormone secretion

cytokines belonging to more than one family (see Table

from the HPA axis, 2 ) under what physiological/patho-

3). For example, IL-6 is not only an interleukin, but also

physiological circumstances endogenous cytokines may

a member of a family of either hematopoietic or (neuro-

inﬂuence HPA axis secretory activity, 3 ) at which level

poietic) factors that utilize an identical receptor subunit

(hypothalamus, pituitary, or adrenal) cytokines primarily

(gp130) for cell signaling (416). Furthermore, IL-1, IL-3,

act, and 4 ) what anatomic and pharmacological pathways

IL-5, and IL-6 are also CSF.

mediate the actions of cytokines on the neuroendocrine

One of the striking features of cytokines is their abil-

hypothalamus. To achieve this aim, we have divided this

ity to exert many different actions (a property known as

article into sections corresponding to these overall objec-

‘‘pleiotropy’’) and, conversely, that many different cyto-

tives. We begin by providing brief introductions to rele-

kines exert the same biological actions (a property known

vant aspects of cytokine biology (see sect. I C ) and the

as ‘‘redundancy’’) (162, 633). Cytokine pleiotropy presum-

functional anatomy of the HPA axis (see sect. I D ).

ably relates to the widespread distribution of cytokine

receptors on numerous cell types and the ability of signal

transduction mechanisms activated by cytokines to alter

C. Cytokines

expression of a wide variety of target genes. The func-

tional redundancy of various cytokines has, at least par-

1. Cytokines and cytokine receptor families

tially, been explained by the identiﬁcation and molecular

cloning of many cytokine receptors. Some, although cer-

Cytokines are large (8 – 60 kDa), soluble polypeptide

mediators that regulate growth, differentiation, and func- tainly not all, cytokine receptors consist of a multiunit

complex, including a cytokine-speciﬁc ligand binding

tion of many different cell types (see Table 3). The major-

ity of cytokines have been classically associated with the component and a ‘‘class’’-speciﬁc signal transduction unit

(416, 733). In addition to the gp130 signaling cytokines,

regulation of immune and/or inﬂammatory processes, and

within the immune system, their actions are generally ex- common receptor subunits have also been demonstrated

for IL-2, IL-4, and IL-7 (733) and also for IL-3, IL-5, and

erted in paracrine or autocrine fashions. However, be-

cause of the demonstration that immune, central nervous, granulocyte-macrophage CSF which share the signal

transduction subunit KH7 (552). However, cytokine re-

and neuroendocrine systems share a common chemical

language, much more diverse actions of cytokines in host dundancy cannot be totally explained by the sharing of

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