Selective involvement of interleukin-6 in the transcriptional activation of the suppressor of cytokine signaling-3 in the brain during systemic immune challenges
E. Lebel et al., Selective involvement of interleukin-6 in the transcriptional activation of the suppressor of cytokine signaling-3 in the brain during systemic immune challenges, ENDOCRINOL, 141(10), 2000, pp. 3749-3763
Cytokine-inducible proteins named as suppressors of cytokine signaling (SOC
S) are rapidly induced by interleukin-6 (IL-6) and other members sharing th
e gp130 receptor subunit after activation of the Janus kinases (JAK) and th
e signal transducers and activators of transcription (STAT). These inhibito
ry proteins generally prevent tyrosine phosphorylation of IL-6 receptor sig
naling subunit gp130, specific JAK and STAT or in acting at steps distal to
JAK activation. Expression of these inhibitory proteins is therefore a use
ful tool to investigate the signaling events occurring in the brain during
immunogenic stimuli that involve cytokines of the IL-6 family. This study i
nvestigated the effect of ip lipopolysaccharide (LPS) administration on the
expression of one key member of the SOCS family, SOCS-3, in both rats and
mice. In rats, the endotoxin caused a profound transcriptional activation o
f the inhibitory factor in the circumventricular organs subfornical organ,
organum vasculosum of the lamina terminalis, arcuate nucleus/median eminenc
e, area postrema, choroid plexus, leptomeninges, ependymal lining cells, an
d along the endothelium of the brain blood vessels. The hybridization signa
l for SOCS-3 messenger RNA was low at 1 h, but robust at 3 and 6 h and decl
ined to return to basal levels 12 h after the single ip LPS injection. The
pattern of SOCS-3 expression was similar in the brain of wildtype mice, alt
hough induction of the inhibitory factor was no longer observed in the epen
dymal lining cells of the cerebral ventricles and the blood microvessels of
IL-6-deficient animals at an the times evaluated, i.e. from 1-8 h post-LPS
injection. The endothelium of the brain capillaries also exhibited up-regu
lation of both IL-6 receptor and gp130 subunits during systemic inflammatio
n, which allowed SOCS-3 expression in response to circulating IL-6. The pre
sent data indicate that the JAK/STAT transduction pathways that lead to SOC
S-3 transcription are activated within cells accessible from the blood circ
ulation, but not within deep parenchymal elements of the brain during endot
oxemia. Induction of SOCS-3 followed the cascade of events that take place
during the acute phase response and the contribution of IL-6 in activating
the inhibitory factor is site specific and not generalized throughout the c
entral nervous system.