Glucocorticoids Induce a TH2 Response In Vitro
Glucocorticoids Induce a Th2 Response In Vitro
FRANCISCO RAMREZ 0
0 Medical Research Council, Cellular Immunology Unit, Sir William Dunn School of Pathology, University of Oxford , South Parks Road, Oxford OX1 3RE
Purified rat CD4 T cells were activated in vitro, by the polyclonal mitogen Concanavalin A (Con A) or by mixed lymphocyte reaction (MLR), in the presence or absence of the glucocorticoid dexamethasone (DEX). They were then expanded in IL-2 and subsequently restimulated, this time in the absence of the hormone. The results indicate that the exposure of the cells to DEX in the primary stimulation changed the cytokine synthesis induced by the secondary stimulation. IL-4 production was increased by the pretreatment whereas synthesis of IFN-y was diminished. Addition of DEX in the second activation suppressed all cytokine production. In brief, the transient presence of glucocorticoids in the culture induces a change in the pattern of cytokine production but the continuous presence causes inhibition of cytokine synthesis. Further studies in which IL-4 was used together with DEX showed that the cytokine potentiated the effect of the hormone. The data here presented suggest that glucocorticoids and the neuroendocrine system may be expected to have long-term immunological effects as well as short-lived immunosuppressive ones. High concentration of glucocorticoids suppress cytokine production but when steroids return to basal levels the immune response is directed in a way that favors Th2-type reactions. Possible implications regarding the immune response to pathogens and autoantigens are discussed.
Activation; CD4 T cells; cytokines; glucocorticoids
INTRODUCTION reaction (Munck et al., 1984). During the course of an immune response corticoid secretion from the adrenal
Understanding the influence of glucocorticoids on the
glands is increased and this mechanism limits the
immune system is important for two reasons: first,
magnitude of the inflammatory reaction to an
immucorticosteroids are used as immunosuppressive and
nogenic stimulus
(Besedovsky et al., 1975)
.
Followanti-inflammatory agents in organ transplantation and
ing activation of the immune system several soluble
in the treatment of many autoimmune and
inflammafactors that activate the neuroendocrine system are
tory diseases. Second, it is not commonly recognised
released
(Besedovsky et al,., 1981)
. Partial failures in
that, in addition to their pharmacological actions,
this interaction between the immune and
neuroendothese steroids are natural hormones that play an
crine systems contribute to the pathogenesis of certain
essential physiological role in the regulation of the
autoimmune and inflammatory experimental diseases
immune system. Release of endogenous
glucocorlike thyroiditis, arthritis and experimental allergic
ticoids protects us against our own defense
mechanisms by preventing an excessive immunological
encephalomyelitis (EAE)
(Kroemer et al., 1988;
MacPhee et al., 1989; Sternberg et al., 1989; Mason et
al., 1990)
. There are also evidences that patients with
rheumatoid arthritis show a defective regulation of
corticosteroids production
(Chikanza et al., 1992)
.
Our interest in the role of corticosteroids in the
regulation of the immune response originated from
the study of EAE in Lewis rats. EAE is an animal
model of autoimmune disease, similar to multiple
sclerosis, that can be induced in the appropriate
animal strains after immunization with myelin basic
protein (MBP) in complete Freund?s adjuvant. EAE in
Lewis rats is a monophasic disease characterized by a
single episode of paralysis, caused by the action of
CD4 T lymphocytes on the nervous system, followed
by spontaneous recovery. Animals that have
recovered are refractory to attempts to induce further
episodes of disease
(Zamvil and Steinman, 1990)
. The
mechanisms responsible for the spontaneous recovery
and the maintenance of the refractory state, although
object of intense research, are not completely
understood. One mechanism that controls the course of
EAE is neuroendocrine-mediated immunoregulation.
It has been shown that endogenously produced
corticosterone plays an essential role in the recovery
of rats from EAE: Unlike normal rats,
adrenalectomized animals do not recover spontaneously but
instead develop a progressive paralysis with a fatal
consequence.
If these animals are administered corticosterone,
they recover and become refractory to the
development of new episodes of disease
(Levine et al., 1980;
MacPhee et al., 1989)
. The spontaneous recovery of
rats from EAE probably occurs because
corticosteroids, which are found at high levels in the sera of
paralyzed animals, acutely depress the autoimmune
response through their immunosuppressive effects.
However, animals that have recovered from disease
have normal serum steroid levels indicating that
corticosteroids are not directly responsible for the
maintenance of the refractory phase of the disease.
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