TY - JOUR T1 - IL-23 production is regulated via an MSK1/2 – CREB dependent signalling pathway downstream of Toll like receptors JF - bioRxiv DO - 10.1101/2020.07.07.189142 SP - 2020.07.07.189142 AU - Kirsty F. Houslay AU - Manuel van Gijsel-Bonnello AU - Tsvetana Petrova AU - Shaista Naqvi AU - J. Simon C. Arthur Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/07/2020.07.07.189142.abstract N2 - IL-23 is an IL-12 family cytokine that is important in promoting Th17 responses and has been strongly linked to autoimmunity and psoriasis. It is a heterodimeric cytokine made up of a p19 subunit unique to IL-23 and a p40 subunit that is shared with IL-12. We show here that in response to LPS, the induction of IL-23p19 mRNA is regulated by a MSK1/2 – CREB dependent pathway downstream of ERK1/2 and p38α MAPK. Knockout of MSK1/2 resulted in a decrease in both IL-23p19 mRNA transcription and IL-23 secretion in GM-CSF differentiated bone marrow cells. Similar effects were seen when the MSK1/2 phosphorylation site in CREB was mutated to alanine. Stimulation with PGE2 promotes the nuclear localisation of CRTC3, a co-activator for CREB. In combination with LPS, PGE2 promoted IL-23p19 mRNA transcription and this was blocked by knockdown of CRTC3. Imiquimod induced skin inflammation in mice has been used as a model for psoriasis and is dependent on IL-23. While MSK1/2 knockout reduced the induction of IL-23 in vivo following i.p. injection of LPS, the knockout mice were not protected from Imiquimod induced skin inflammation. MSK1/2 knockout did not reduce the induction of IL-17 producing γδT cells following Imiquimod treatment, although MSK1/2 knockout did reduce the levels of these cells in mice receiving a control cream. The lack of protection in the Imiquimod model may be due to the known anti-inflammatory roles or MSKs, such as its contribution to the induction of IL-10.Competing Interest StatementThe authors have declared no competing interest. ER -