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. 2006 Apr 5;12(4):420–429. doi: 10.1111/j.1750-3639.2002.tb00459.x

The Critical Role of IL‐12p40 in Initiating, Enhancing, and Perpetuating Pathogenic Events in Murine Experimental Autoimmune Neuritis

Lei Bao 1,2, J Urban Lindgren 2, Peter van der Meide 4, Shun Wei Zhu 1, Hans‐Gustaf Ljunggren 3, Jie Zhu 1,✉
PMCID: PMC8095878  PMID: 12408228

Abstract

Interleukin 12 (IL‐12) is a proinflammatory cytokine with important immunoregulatory activities and is critical in determining the differentiation and generation of Th1 cells. For the present study, we investigated the role of endogenous IL‐12 in the pathogenesis of experimental autoimmune neuritis (EAN), which is a CD4+ T‐cell mediated autoimmune inflammatory disease of the peripheral nervous system. EAN is used as an animal model for Guillain‐Barré syndrome of humans. Here, EAN was established in IL‐12 p40 deficient mutant (IL‐12‐/‐) C57BL/6 mice by immunization with P0 peptide 180–199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. In these IL‐12‐/‐ mice the onset of clinical disease was delayed, and the incidence and severity of EAN were significantly reduced compared to that in wild‐type mice. The former group's clinical manifestations were associated with less P0‐peptide 180–199 induced secretion of interferon‐γ (IFN‐γ) by splenocytes in vitro and low production of anti‐P0‐peptide 180–199 IgG2b antibodies in serum. Fewer IFN‐γ and TNF‐α producing cells, but more cells secreting IL‐4, were found in sciatic nerve sections from IL‐12‐/‐ mice, consistent with impaired Th1 functions and response. However, the IL‐12 deficiency appeared not to affect P0 peptide 180–199‐specific T‐cell proliferation. These results indicate that IL‐12 has a major role in the initiation, enhancement and perpetuation of pathogenic events in EAN by promoting a Th1 cell‐mediated immune response and suppressing the Th2 response. This information augments consideration of IL‐12 as a therapeutic target in Guillain‐Barré syndrome and other T‐cell‐mediated autoimmune diseases.

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References

  • 1. Bai XF, Zhu J, Zhang GX, Kaponides G, Höjeberg B, van der Meide PH, Link H (1997) IL‐10 suppresses experimental autoimmune neuritis, and down‐regulates Th1‐type immune responses. Clin Immunol Immunopathol 2:117–126. [DOI] [PubMed] [Google Scholar]
  • 2. Calida DM, Kremlev SG, Fujioka T, Hilliard B, Ventura E, Constantinescu CS, Lavi E, Rostami A (2000) Experimental allergic neuritis in the SJL/J mouse: induction of severe and reproducible disease with bovine peripheral nerve myelin and pertussis toxin with or without interleukin‐12. J Neuroimmunol 107:1–7. [DOI] [PubMed] [Google Scholar]
  • 3. Constantinescu CS, Frei K, Wysocka M, Trinchieri G, Malipiero U, Rostami AM, Fontana A (1996) Astrocytes and microglia produce IL‐12 p40. Ann NY Acad Sci 795:328–333. [DOI] [PubMed] [Google Scholar]
  • 4. Constantinescu CS, Hilliard B, Ventura E, Wysocka M, Showe L, Lavi E, Fujioka T, Scott P, Trinchieri G, Rostami A (2001) Modulation of susceptibility and resistance to an autoimmune model of multiple sclerosis in prototypically susceptible and resistant strains by neutralization of interleukin‐12 and interleukin‐4, respectively. Clin Immunol 98:23–30. [DOI] [PubMed] [Google Scholar]
  • 5. Debra MB, Anne MM, Ravinder NM, Fionula MB and Marc F (1999) Anti‐IL‐12 and anti‐TNF antibodies synergistically suppress the progression of murine collagen‐induced arthritis. Eur J Immunol 29:2205–2212. [DOI] [PubMed] [Google Scholar]
  • 6. Deretzi G, Zou LP, Pelidou SH, Nennesmo I, Levi M, Wahren B, Mix E, Zhu J (1999) Nasal administration of recombinant rat IL‐4 ameliorates ongoing experimental autoimmune neuritis and inhibits demyelination. J Autoimmun 1 2:81–89. [DOI] [PubMed] [Google Scholar]
  • 7. Du C, Cooper JC, Klaus SJ and Sriram S (2000) Amelioration of CR‐EAE with lisofylline: effects on mRNA levels of IL‐12 and IFN‐gamma in the CNS. J Neuroimmunol 110:13–19. [DOI] [PubMed] [Google Scholar]
  • 8. Hsieh C‐S, Macatonia SE, Tripp CS, Wolf SF, O'Garra A and Murphy KM (1993) Development of TH1 CD4+ T‐cells through IL‐12 produced by Listeria‐induced macrophages. Science 260:547–549. [DOI] [PubMed] [Google Scholar]
  • 9. Germann T, Szeliga J, Hess H, Storkel S, Podlaski FJ, Gately MK (1995) Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci U S A 92:4823–4827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Jeanne M, Suzanne EC, Rajeev RW, Daisy MC, Chang YW, Jessica F, Colin S, Ulla S, Denise AF, and Maurice KG (1996) IL‐12‐Deficient mice are defective in IFN‐γ production and type 1 cytokine responses. Immunity 4: 471–481. [DOI] [PubMed] [Google Scholar]
  • 11. Jee Y and Matsumoto Y (2001) Two‐step activation of T‐cells, clonal expansion ad subsequent Th1 cytokine production, is essential for the development of clinical autoimmune encephalomyelitis. Eur J Immunol 31:1800–1812. [DOI] [PubMed] [Google Scholar]
  • 12. Jelinek DF, and Braaten JK (1995) Role of IL‐12 in human B lymphocyte proliferation and differentiation. J Immunol 154:1606–1613. [PubMed] [Google Scholar]
  • 13. Leonard JP, Waldburger KE, Goldman SJ (1995) Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 181:381–386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Manetti R, Parronchi P, Giudizi MG, Piccinni M‐P, Maggi E, Trinchieri G, Romagnani S (1993) Natural killer cell stimulatory factor (interleukin 12) induces T helper type 1 (Th1)‐specific immune responses and inhibits the development of IL‐4 producing Th cells. J Exp Med 177:1199–1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. O'Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283. [DOI] [PubMed] [Google Scholar]
  • 16. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, De Waal‐Malefyt R, Hannum C, Bazan JF, Kastelein RA. (2000) 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. [DOI] [PubMed] [Google Scholar]
  • 17. Pelidou SH, Deretzi G, Zou LP, Quiding C, Zhu J (1999) Inflammation and severe demyelination in peripheral nervous system induced by the intraneural injection of recombinant mouse IL‐12. Scan J Immunol 50:39–44. [DOI] [PubMed] [Google Scholar]
  • 18. Pelidou SH, Zou LP, Deretzi G, Nennesmo I, Wei L, Mix E, Zhu J (2000) Nasal administration of recombinant mouse IL‐12 increases inflammation and demyelination in chronic experimental autoimmune neuritis in Leiws rats. Scan J Immunol 51:29–35. [DOI] [PubMed] [Google Scholar]
  • 19. Previtali SC, Feltri ML, Archelos JJ, Quattrini A, Wrabetz L, Hartung H (2001) Role of integrins in the peripheral nervous system. Prog Neurobiol 64:35–49. [DOI] [PubMed] [Google Scholar]
  • 20. Romagnani S (1997) The Th1/Th2 paradigm. Immunol Today 18:263–266. [DOI] [PubMed] [Google Scholar]
  • 21. Segal BM, Dwyer BK and Shevach EM (1998) An interleukin (IL)‐10/IL‐12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187:537–546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Sypek JP, Chung CL, Mayor SHE, Subramanyam JM, Goldman SJ, Sieburth DS, Wolf SF, Schaub RG (1993) Resolution of cutaneous leishmaniasis: interleukin‐12 initiates a protective T helper type 1 immune response. J Exp Med 177:1797–1802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Tarrant TK, Silver PB, Chan C‐C, Wiggert B and Caspi RR (1998) Endogenous IL‐12 is required for induction and expression of experimental autoimmune uveitis. J Immunol 161:122–127. [PubMed] [Google Scholar]
  • 24. Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L (1995) Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 181:817–821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Trinchieri G (1993) Interleukin‐12 and its role in the generation of Th‐1 cells. Immunol Today 14:335–338. [DOI] [PubMed] [Google Scholar]
  • 26. Trinchieri G (1995) Interleukin‐12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen‐specific adaptive immunity. Annu Rev Immunol 13:251–276. [DOI] [PubMed] [Google Scholar]
  • 27. Trinchieri G (1998) Interleukin‐12: a cytokine at the interface of inflammation and immunity. Adv Immunol 70:83–243. [DOI] [PubMed] [Google Scholar]
  • 28. Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM, Kelleher K, Herrmann SH, Clark SC, Azzoni L, Chan SH, Trinchieri G and Perussia B (1991) Cloning of cDNA for natural kill cell stimulatory factor, a heterodimeric cytokine with multiple biological effects on T and natural killer cells. J Immunol 146:3074–3081. [PubMed] [Google Scholar]
  • 29. Yang J, Murphy TL, Ouyang W, Murphy KM (1999) Induction of interferon‐γ production in Th1 CD4+ T‐cells: evidence for two distinct pathways for promoter activation. Eur J Immunol 29:548–555. [DOI] [PubMed] [Google Scholar]
  • 30. Yu S, Chen Z‐G, Mix E, Zhu S‐W, Winblad B, Ljunggren H‐G, Zhu J. (2002) Neutralizing antibodies to IL‐18 ameliorates experimental autoimmune neuritis by counter‐regulation of antoreactive Th1 responses to peripheral myelin antigen. J Neuropathol Exp Neurol 61:614–622. [DOI] [PubMed] [Google Scholar]
  • 31. Zhu J, Bai XF, Mix E, Link H (1997) Experimental allergic neuritis: Cytolysin mRNA expression is upregulated in lymph node cells during convalescence. J Neuroimmunol 78:108–116. [DOI] [PubMed] [Google Scholar]
  • 32. Zhu J, Bai XF, Mix E, Link H (1997) Cytokine dichotomy in the peripheral nervous system influences the outcome of experimental allergic neuritis: dynamics of mRNA expression for IL‐1β, IL‐6, IL‐10, IL‐12, TNF‐α and TNF‐β and cytolysin. Clin Immunol Immunopathol 84:85–94. [DOI] [PubMed] [Google Scholar]
  • 33. Zhu J, Mix E, and Link H (1998) Cytokine production and the pathogenesis of experimental allergic neuritis and Guillain‐Barre syndrome. J Neuroimmunol 84: 40–52. [DOI] [PubMed] [Google Scholar]
  • 34. Zhu J, Bai XF, Hedlund G, Björk J, Bakhiet M, van der Meide P, Link H (1999) Linomide suppresses experimental allergic neuritis in Lewis rats by inhibiting myelin antigen‐reactive T and B cells responses. Clin Exp Immunol 1: 56–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Zhu J, Zou LP, Zhu SW, Mix E, Shi FD, Wang HB, Volkmann I, Winblad B, Schalling M, Ljunggren HG (2001) Cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4) blockade enhances incidence and severity of experimental autoimmune neuritis in resistant mice. J Neuroimmunol 115:111–117. [DOI] [PubMed] [Google Scholar]
  • 36. Zhu Y, Ljunggren HG, Mix E, Li HL, van der Meide P, Elhassan AM, Winblad B, Zhu J (2001) CD28/B7 costimulation: a critical role for initiation and development of experimental autoimmune neuritis in C57BL/6 mice. J Neuroimmunol 114:114–121. [DOI] [PubMed] [Google Scholar]

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