The family of
interleukin 17 receptors (IL17Rs), subtypes IL17RA-IL17RE, is targeted by the group of pro-inflammatory IL17
cytokines (IL17A-F) and moreover the newly developed anti-IL17A antibody
secukinumab (
AIN457) has shown promise in Phase II trials in
multiple sclerosis. Here, we show that human astrocytes, isolated from a fetal cerebral cortex, express IL17RA and IL17RC and in vitro treatment with IL17A increases
protein levels of
IL6 in human astrocytes, which is enhanced in the presence of TNFα, as determined by homogeneous time resolved fluorescence. Studies on acutely isolated mouse astrocytes are comparable to human astrocytes although the
protein levels of
IL6 are lower in mouse astrocytes, which also show a lower response to IL17F and IL1β in promoting
IL6 levels. In human astrocytes, IL17A and TNFα also induce
mRNA expression of
IL6,
IL8 and the Th17
cytokines CXCL1, CXCL2, and CCL20, with little effect on Th1
cytokines CXCL9, CXCL10, and CXCL11. The effects of IL17A are associated with nuclear translocation of the NF-κB
transcription factor, as determined by immunocytochemistry, where treatment of human astrocytes with the inhibitors of the NF-κB pathway and with
secukinumab inhibits the IL17A and IL17A/TNFα-induced increase in nuclear translocation of NF-κB and levels of
IL6. Taken together the data shows that IL17A signaling plays a key role in regulating the levels of
cytokines, such as
IL6, in human astrocytes via a mechanism that involves NF-κB signaling and that selective inhibition of IL17A signaling attenuates levels of pro-inflammatory molecules in astrocytes.