Selective involvement of interleukin-6 in the transcriptional activation of the suppressor of cytokine signaling-3 in the brain during systemic immune challenges

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.