Focus on Inflammatory Disease

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

Journal name:
Nature Medicine
Year published:
Published online


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.

At a glance


  1. Schematic representation of IL-12 and IL-23, and their receptors and downstream signaling pathways.
    Figure 1: Schematic representation of IL-12 and IL-23, and their receptors and downstream signaling pathways.

    IL-12 is made up of the IL-12/23p40 and IL-12p35 subunits, and IL-23 comprises IL-23p19 and IL-12/23p40. IL-12 signals through the IL-12Rβ1 and IL-12Rβ2 subunits, and IL-23 signals through IL-12Rβ1 and IL-23R. IL-12 stimulation of JAK2 and TYK2 activity leads to phosphorylation of STAT4 and other STAT molecules. IL-23 also activates the JAK-STAT pathway but acts mainly on STAT3. IL-12 induces the production of IFN-γ, which is required for the development of TH1 immune response. IL-23 induces IL-17A, IL-17F and/or IL-22 and stabilizes TH17 cells.

  2. Efficacy of IL-12/23p40, IL-23p19 and IL-17A or IL-17RA antagonists in treating patients with moderate-to-severe psoriasis.
    Figure 2: Efficacy of IL-12/23p40, IL-23p19 and IL-17A or IL-17RA antagonists in treating patients with moderate-to-severe psoriasis.

    IL-23 and IL-23 pathway antagonists demonstrate substantial benefit for a large fraction of patients with moderate to severe psoriasis. Phase 3 results are from week 12; phase 2 results are from week 16 (tildrakizumab and guselkumab) or week 12. The highest reported efficacy for any dose group within the studies' 12–16 week treatment period is plotted. Black bar within each colored histogram indicates the associated placebo group. Ustekinumab's phase 3 results are from PHOENIX-I and PHOENIX-II70, 71. Briakinumab's phase 3 results are from clinical trials NCT00570986 (ref. 72), NCT00691964 (ref. 73), NCT00679731 (ref. 74) and NCT00710580 (ref. 75). Secukinumab's phase 3 results are from the ERASURE83, FIXTURE83, FEATURE84 and JUNCTURE84 trials. Ixekizumab's phase 3 results are from UNCOVER-I, UNCOVER-II and UNCOVER-III85. Each individual study's efficacy has not been stated but the range of efficacy seen over the three studies has been stated (the graphed bar is the mean and the error bar is the range between the three studies' efficacy). Brodalumab's phase 3 results are from AMAGINE-I86. Tildrakizumab's phase 2 results are from NCT01225731, week 16. Guselkumab's phase 2 results are from X-PLORE77, week 16. Secukinumab's phase 2 results are from NCT00941031 (ref. 80) and NCT01071252 (ref. 81), week 12. Ixekizumab's phase 2 results are from NCT01107457 (ref. 79), week 12. Brodalumab's phase 2, week 12 results are from NCT00975637 (ref. 82), week 12.

  3. Pathogens that have been identified as causing infections in patients with IL-12/23p40 (n = 49) or IL-12R[beta]1 (n = 170) deficiency.
    Figure 3: Pathogens that have been identified as causing infections in patients with IL-12/23p40 (n = 49) or IL-12Rβ1 (n = 170) deficiency.

    X axis indicates the number of patients with each infection. Some patients with IL-12Rβ1 deficiency have multiple infections.

  4. Schematic representation of the mechanisms by which IL-23 indirectly or directly promotes tumorigenesis, growth and metastasis.
    Figure 4: Schematic representation of the mechanisms by which IL-23 indirectly or directly promotes tumorigenesis, growth and metastasis.

    IL-23 is produced by myeloid cells in response to exogenous or endogenous signals such as damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) or tumor-secreted factors such as prostaglandin E2 (PGE2). IL-23 can act directly on tumor cells to promote their transformation, proliferation and/or metastasis. In mice, IL-23R is expressed on several innate and adaptive immune cell types, which are found in various proportions in tumors. Stimulation of IL-23R on these immune cells leads to production of cytokines such as IL-17 and/or IL-22, which can have direct proliferative effects on stromal or tumor cells. IL-17 and/or IL-22 also elicit a range of factors from various hematopoietic and nonhematopoietic cells, which can have direct effects on tumor proliferation and metastasis or induce the production of additional inflammatory cytokines, chemokines and mediators such as IL-6, IL-8, matrix metallopeptidases (MMPs) and vascular endothelial growth factor (VEGF), all of which can contribute to the generation of a tumor microenvironment in which CD8 and NK cell effector functions are suppressed. DC, dendritic cell; Mφ, macrophage.


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  1. Cancer Immunoregulation and Immunotherapy and Immunology in Cancer and Infection Laboratories, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

    • Michele W L Teng &
    • Mark J Smyth
  2. School of Medicine, University of Queensland, Herston, Queensland, Australia.

    • Michele W L Teng &
    • Mark J Smyth
  3. Merck Research Laboratories, Palo Alto, California, USA.

    • Edward P Bowman &
    • Daniel J Cua
  4. Merck Research Laboratories, Boston, Massachusetts, USA.

    • Joshua J McElwee
  5. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

    • Jean-Laurent Casanova
  6. Howard Hughes Medical Institute, New York, New York, USA.

    • Jean-Laurent Casanova
  7. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.

    • Jean-Laurent Casanova
  8. Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, Paris, France.

    • Jean-Laurent Casanova
  9. Paris Descartes University, Imagine Institute, Paris, France.

    • Jean-Laurent Casanova
  10. Trudeau Institute, Inc., Saranac Lake, New York, USA.

    • Andrea M Cooper

Competing financial interests

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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