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Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

Abstract

Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-γ (refs 1, 2). Similarly, numerous studies3,4,5,6,7 have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit8, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression9 and IL-23 overexpression in transgenic mice10 suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.

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Figure 1: Generation of IL-23-deficient mice.
Figure 2: IL-23, and not IL-12, is required for the induction of EAE.
Figure 3: TH1 cells are induced in p19-/- but not p35-/- mice.
Figure 4: TH1 cells and inflammatory macrophages enter the CNS of MOG-immunized p19-/- mice but fail to induce EAE.
Figure 5: IL-23, and not IL-12, induces IL-1β and TNF mRNA expression in macrophages.

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References

  1. Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989)

    Article  CAS  Google Scholar 

  2. Trinchieri, G. et al. Natural killer cell stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune response and inflammation. Prog. Growth Factor Res. 4, 355–368 (1992)

    Article  CAS  Google Scholar 

  3. Leonard, J. P., Waldburger, K. E. & Goldman, S. J. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J. Exp. Med. 181, 381–386 (1995)

    Article  CAS  Google Scholar 

  4. Issazadeh, S., Ljungdahl, A., Hojeberg, B., Mustafa, M. & Olsson, T. Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumour necrosis factor α and tumour necrosis factor β. J. Neuroimmunol. 61, 205–212 (1995)

    Article  CAS  Google Scholar 

  5. Leonard, J. P., Waldburger, K. E. & Goldman, S. J. Regulation of experimental autoimmune encephalomyelitis by interleukin-12. Ann. NY Acad. Sci. 795, 216–226 (1996)

    Article  ADS  CAS  Google Scholar 

  6. Constantinescu, C. S. et al. Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J. Immunol. 161, 5097–5104 (1998)

    CAS  Google Scholar 

  7. Segal, B. M., Dwyer, B. K. & Shevach, E. M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546 (1998)

    Article  CAS  Google Scholar 

  8. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000)

    Article  CAS  Google Scholar 

  9. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002)

    Article  CAS  Google Scholar 

  10. Wiekowski, M. T. et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J. Immunol. 166, 7563–7570 (2001)

    Article  CAS  Google Scholar 

  11. Cua, D. J., Hutchins, B., LaFace, D. M., Stohlman, S. A. & Coffman, R. L. Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis. J. Immunol. 166, 602–608 (2001)

    Article  CAS  Google Scholar 

  12. O'Garra, A. & Arai, N. The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol. 10, 542–550 (2000)

    Article  CAS  Google Scholar 

  13. Caspi, R. R. IL-12 in autoimmunity. Clin. Immunol. Immunopathol. 88, 4–13 (1998)

    Article  CAS  Google Scholar 

  14. Falcone, M. & Sarvetnick, N. Cytokines that regulate autoimmune responses. Curr. Opin. Immunol. 11, 670–676 (1999)

    Article  CAS  Google Scholar 

  15. Willenborg, D. O., Fordham, S., Bernard, C. C., Cowden, W. B. & Ramshaw, I. A. IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol. 157, 3223–3227 (1996)

    CAS  Google Scholar 

  16. Chu, C. Q., Wittmer, S. & Dalton, D. K. Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J. Exp. Med. 192, 123–128 (2000)

    Article  CAS  Google Scholar 

  17. Matthys, P., Vermeire, K. & Billiau, A. Mac-1+ myelopoiesis induced by CFA: a clue to the paradoxical effects of IFN-γ in autoimmune disease models. Trends Immunol. 22, 367–371 (2001)

    Article  CAS  Google Scholar 

  18. Hickey, W. F., Hsu, B. L. & Kimura, H. T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28, 254–260 (1991)

    Article  CAS  Google Scholar 

  19. Sedgwick, J. D. et al. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc. Natl Acad. Sci. USA 88, 7438–7442 (1991)

    Article  ADS  CAS  Google Scholar 

  20. Frucht, D. M. IL-23: a cytokine that acts on memory T cells. Sci. STKE 114 (2002) pe1 [online] 〈http://stke.sciencemag.org/〉 (2002)

  21. Nguyen, K. B. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-γ response to viral infection. Science 297, 2063–2066 (2002)

    Article  ADS  CAS  Google Scholar 

  22. Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001)

    Article  ADS  CAS  Google Scholar 

  23. Chen, Q. et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000)

    Article  ADS  CAS  Google Scholar 

  24. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002)

    Article  CAS  Google Scholar 

  25. Holscher, C. et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J. Immunol. 167, 6957–6966 (2001)

    Article  CAS  Google Scholar 

  26. Piccotti, J. R. et al. Alloantigen-reactive Th1 development in IL-12-deficient mice. J. Immunol. 160, 1132–1138 (1998)

    CAS  Google Scholar 

  27. Becher, B., Durell, B. G. & Noelle, R. J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002)

    Article  CAS  Google Scholar 

  28. Chen, S. C. et al. Impaired pulmonary host defense in mice lacking expression of the CXC chemokine lungkine. J. Immunol. 166, 3362–3368 (2001)

    Article  CAS  Google Scholar 

  29. Hickey, W. F. Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol. 1, 97–105 (1991)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Cupp and the DNAX FACS Facility; and K. Moore, G. Zurawski and D. Rennick for comments. DNAX Research Inc. is supported by Schering-Plough.

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Correspondence to Daniel J. Cua.

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Cua, D., Sherlock, J., Chen, Y. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003). https://doi.org/10.1038/nature01355

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