title: The selective anti-IL17A monoclonal antibody secukinumab (AIN457) attenuates IL17A-induced levels of IL6 in human astrocytes.
abstract: 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.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Elain
authors.forename: Karine
authors.initials: K
authors.lastname: Jeanneau
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rutkowska
authors.forename: Anis K
authors.initials: AK
authors.lastname: Mir
authors.forename: Kumlesh K
authors.initials: KK
authors.lastname: Dev
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508717:IL17A protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D015850:Interleukin-6; C555450:secukinumab