Proinflammatory
cytokines and serotonergic homeostasis have both been implicated in the pathophysiology of major
psychiatric disorders. We have demonstrated that activation of
p38 mitogen-activated protein kinase (MAPK) induces a catalytic activation of the
serotonin transporter (SERT) arising from a reduction in the SERT Km for
5-hydroxytryptamine (5-HT). As inflammatory
cytokines can activate
p38 MAPK, we hypothesized that they might also activate neuronal SERT. Indeed,
Interleukin-1beta (IL-1beta) and
tumor necrosis factor alpha (
TNF-alpha) stimulated
serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1beta stimulated
5-HT uptake in a dose- and time-dependent manner, peaking in 20 min at 100 ng/ml. This was abolished by
IL-1ra (20 ng/ml), an antagonist of the
IL-1 receptor, and by
SB203580 (5 microM), a
p38 MAPK inhibitor.
TNF-alpha also dose- and time-dependently stimulated
5-HT uptake that was only partially blocked by
SB203580. Western blots showed that IL-1beta and
TNF-alpha activated
p38 MAPK, in an SB203580-sensitive manner. IL-1beta induced an SB203580-sensitive decrease in
5-HT Km with no significant change in Vmax. In contrast,
TNF-alpha stimulation decreased
5-HT Km and increased SERT Vmax.
SB203580 selectively blocked the
TNF-alpha-induced change in SERT Km. In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on
5-HT uptake occurred at lower concentrations (IL-1beta, 10 ng/ml;
TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1beta and
TNF-alpha were completely (IL-1beta) or partially (
TNF-alpha) blocked by
SB203580. These results provide the first evidence that proinflammatory
cytokines can acutely regulate neuronal SERT activity via
p38 MAPK-linked pathways.