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IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases

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Abstract

The cytokine interleukin-12 (IL-12) was thought to have a central role in T cell–mediated responses in inflammation for more than a decade after it was first identified. Discovery of the cytokine IL-23, which shares a common p40 subunit with IL-12, prompted efforts to clarify the relative contribution of these two cytokines in immune regulation. Ustekinumab, a therapeutic agent targeting both cytokines, was recently approved to treat psoriasis and psoriatic arthritis, and related agents are in clinical testing for a variety of inflammatory disorders. Here we discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders.

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Figure 1: Schematic representation of IL-12 and IL-23, and their receptors and downstream signaling pathways.
Figure 2: Efficacy of IL-12/23p40, IL-23p19 and IL-17A or IL-17RA antagonists in treating patients with moderate-to-severe psoriasis.
Figure 3: Pathogens that have been identified as causing infections in patients with IL-12/23p40 (n = 49) or IL-12Rβ1 (n = 170) deficiency.
Figure 4: Schematic representation of the mechanisms by which IL-23 indirectly or directly promotes tumorigenesis, growth and metastasis.

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Acknowledgements

We thank J. Bustamante and S. Boisson-Dupuis for help in generating some of the figures. M.W.L.T. is supported by a National Health and Medical Research Council of Australia (NH&MRC) CDF1 fellowship and project grants from NH&MRC, and grants from the Prostate Cancer Foundation of Australia and Cancer Council of Queensland (CCQ). M.J.S. is supported by a NH&MRC Program Grant, NH&MRC Senior Principal Research Fellowship, Susan G. Komen and the CCQ.

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D.J.C., J.J.M., and E.P.B. are employed by Merck and Co. M.W.L.T. has received research grants from AMGEN. J.-L.C. has received research grants from Merck. M.J.S. has a scientific research agreement with Bristol-Myers Squibb.

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Teng, M., Bowman, E., McElwee, J. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 21, 719–729 (2015). https://doi.org/10.1038/nm.3895

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