Biology Reference
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the expression of anti-inflammatory cytokines
[108,109]
. Repeated administration of
imipramine in the rat reduced the ability of splenocytes to produce IL-1 and IL-2 fol-
lowing an 8-week exposure to unpredictable mild stress
[110]
. Imipramine, clomip-
ramine, and citalopram can also suppress IL-2 production by stimulated lymphocytes,
and IL-1 and TNF- by stimulated monocytes. Single or repeated administration of
desipramine (10 mg/kg) to naïve mice increased the ability of splenocytes to produce
the anti-inflammatory cytokine IL-10
[111,112]
, and repeated administration of imi-
pramine induced IL-1ra mRNA in the rat brain
[113]
. Human subjects with PTSD
and depression had significantly greater IL-1r and lower IL-2r levels compared with
controls. These values were normalized after treatment with the selective serotonin
reuptake inhibitors (SSRIs) citalopram and sertraline
[114]
. Inhibition of IL-6 release
from monocytes but increased release from lymphocytes has been reported following
incubation with antidepressants such as imipramine, clomipramine, and citalopram.
It is thus possible that these suppress IL-6 production by monocytes but increase its
production by lymphocytes. The cells involved in IL-6 production possess a range
of functional receptors, including those for 5HT, and changes in receptor function/
density induced by alterations in neurotransmitter concentrations may subsequently
affect their activity
[115]
. For example, an association between activation of 5HT
2B/2C
receptors and an increase in IL-6 production has been shown
[116]
. Thus, it may
be speculated that increases in available concentrations of 5HT and in the density
of 5HT receptors, induced by antidepressants such as fluoxetine, may play a role in
the increased production of this cytokine. These findings must nevertheless be inter-
preted cautiously, as only a small number of patients were studied and data from the
depressed patients before and after successful fluoxetine treatment were not available.
In vitro
incubation of whole blood from healthy subjects with SSRIs such as flu-
oxetine and sertraline, the selective noradrenaline reuptake inhibitor venlafaxine, tri-
cyclic antidepressants (imipramine, clomipramine), a reversible monoamine oxidase
inhibitor (moclobemide), and L-5HTP significantly increased the production of IL-10
and/or decreased that of IFN-, thus decreasing the ratio of IFN to IL-10
[117,118]
.
In addition, the 5HT system can inhibit IFN--induced major histocompatibility
(MHC) expression
[119]
and mitogen-induced T-cell proliferation
[120]
. SSRIs also
have inhibitory effects on acute phase protein production
[121]
and on immune sys-
tem activation in general
[122,123]
. More recently,
in vitro
studies have been car-
ried out using whole blood from fluoxetine-treated patients with treatment-resistant
depression, age-matched healthy controls, and younger healthy volunteers, following
stimulation with phytohemagglutinin (PHA) and LPS for 48 hours, with or without
antidepressants. The main findings were that imipramine, venlafaxine, 5-HTP, and a
combination of 5-HTP and fluoxetine increased IL-6 production, whereas none of the
drugs affected TNF-. The production of IL-6 was higher in depressed patients than
in the age-matched controls, whereas TNF- production was significantly higher in
the older volunteers than in the younger subjects
[124]
. The observed stimulant effect
of antidepressants on IL-6 production does not negate the hypothesized relationship
between the therapeutic activity of antidepressants and their immunomodulatory
effect, as IL-6 can inhibit the secretion of the two major pro-inflammatory cytokines
TNF- and IL-1, both of which have established depressogenic effects, and can
