Trans-signaling mediates some key actions of interleukin-6 in the central nervous system (117.6)

Abstract

Abstract IL-6 which is implicated in the pathogenesis of immunoinflammatory disorders of the CNS, signals via binding to either the membrane bound IL-6Rα (classical signaling) or soluble (s)IL-6Rα (trans-signaling) that then form a complex with gp130 to activate the JAK/STAT and SHP2/MAPK pathways. Here we determined the relative importance of classical- versus trans-signaling in mediating IL-6 actions in the CNS. Bigenic mice were generated with CNS-restricted, astrocyte-targeted production of IL-6 and the specific inhibitor of IL-6 trans-signaling, sgp130-Fc (termed GFAP-IL6/sgp130 mice). Transgene-encoded IL-6 mRNA levels were similar in the brain of GFAP-IL6 and GFAP-IL6/sgp130 mice. However, GFAP-IL6/sgp130 mice had decreased pY-STAT3 in the brain due to a marked reduction in the total number of pY-STAT3-positive cells and the absence of detectable pY-STAT3 in specific cell types. These changes in pY-STAT3 were associated with disproportionate reductions in various inflammatory markers as well as reduced vascular pathology and blood-brain barrier leakage. Degenerative changes in the cerebellum characteristic of GFAP-IL6 mice were almost absent in GFAP-IL6/sgp130 mice. The findings suggest that in the CNS: (i) sgp130-Fc is able to block IL-6 trans-signaling, (ii) trans-signaling is important for IL-6 cellular communication with selective cellular targets and, (iii) the blocking of trans-signaling may prove to be an effective means for alleviating the detrimental effects of IL-6.