AB0054 Pde4 inhibitor attenuation of il-23 secretion from mononuclear cells

Background IL-23 is a cytokine heavily implicated in the immunopathology of both psoriasis and psoriatic arthritis. Emerging evidence suggest IL-36λ, a novel inflammatory cytokine which has been heavily implicated in psoriatic immunopathology, is able to stimulate the release of IL-23.1–3 PDE4 inhibitors, which elevate cyclic AMP (cAMP) are known to exert anti-inflammatory effects by regulating transcription factors such as NF-κB. The PDE4 inhibitor, Apremilast has proved successful in treating both psoriasis and psoriatic arthritis with patients showing a decrease in inflammatory cytokine levels, including IL-23.4 However, the ability and mechanism of PDE4 inhibitors to lower IL-23 secretion from immune cells induced by disease relevant stimuli is presently unknown. Additionally, any potential relationship between IL-36λ driven inflammation and potential PDE4 inhibition is yet to be determined. Methods Blood mononuclear cells from healthy patients, (n=5) were pre-treated with either the PDE4 inhibitor Rolipram or other compounds known to elevate cAMP levels, such as histamine and 8-bromo-cAMP. Cells were subsequently treated with either bacterial or fungal toll like receptor adjuvants (LPS and Mannan) or the novel psoriatic cytokine IL-36λ. IL-23 was subsequently measured in culture supernatants by ELISA and by intracellular IL-23p19 flow cytometry. Results LPS, Mannan and IL-36λ all induced IL-23 secretion which could be attenuated in a dose dependent manner by the PDE4 inhibitor, Rolipram. Other compounds also known to increase cAMP levels, histamine and 8-bromo-cAMP similarly were able to reduce IL-23 secretion from all stimuli. Conclusions This data suggests a direct link between PDE4 inhibition and reduced IL-23 secretion in circulating immune cells. Additionally, it provides insight into of how IL36/IL-23/IL-17 driven inflammation may be reduced by PDE4 inhibitors in psoriasis and psoriatic arthritis. References [1] Gabay C, Towne JE. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. J Leukoc Biol2015;97(4):645–652. [2] Chi HH, et al. IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis. J Am Soc Nephrol2017;28(7):2022–2037. [3] Bridgewood C, et al. IL-36γ is a strong inducer of IL-23 production and angiogenesis in psoriasis. Frontiers in Immunology2018;9:200. [4] Keating GM. Apremilast: A Review in Psoriasis and Psoriatic Arthritis. Drugs2017;77(4):459–472. Disclosure of Interest None declared