Skip to main content

Advertisement

Log in

Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes

  • Original Article
  • Published:
Modern Rheumatology

Abstract

Autoantibodies to ribosomal P proteins (anti-P) are detected in 12–16% of patients with systemic lupus erythematosus (SLE), and have been found to be associated with some manifestations, including lupus psychosis, nephritis and hepatitis. We have recently disclosed that anti-P react with activated human peripheral blood monocytes, and enhance their production of tumor necrosis factor-α and interleukin (IL)-6. It is also possible that anti-P might regulate other monocyte functions, including the regulation of T helper (Th) responses. The current study was therefore undertaken to explore the effects of anti-P on the induction of Th1 responses. Peripheral blood mononuclear cells (PBMC) from healthy donors were cultured with affinity-purified anti-P or control IgG. Highly purified monocytes were cultured with interferon (IFN)-γ in the presence of anti-P or normal IgG. Anti-P significantly enhanced the production of IFN-γ by PBMC. Of note, anti-IL-12 monoclonal antibodies almost completely abrogated the anti-P-mediated upregulation of the IFN-γ production of PBMC. Accordingly, anti-P significantly enhanced the production of IL-12 by activated monocytes. These results indicate that anti-P induce Th1 responses by upregulating the production of IL-12 by activated monocytes. The data therefore suggest that anti-P play an important role in the pathogenesis of SLE through the promotion of Th1 responses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Elkon K, Skelly S, Parnassa A, Moller W, Danho W, Weissbach H, et al. Identification and chemical synthesis of a ribosomal protein antigenic determinant in systemic lupus erythematosus. Proc Natl Acad Sci USA. 1986;83:7419–23.

    Article  CAS  PubMed  Google Scholar 

  2. Bonfa E, Golombek SJ, Kaufman LD, Skelly S, Weissbach H, Brot N, et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med. 1987;317:265–71.

    Article  CAS  PubMed  Google Scholar 

  3. Schneebaum AB, Singleton JD, West SG, Blodgett JK, Allen LG, Cheronis JC, et al. Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus. Am J Med. 1991;90:54–62.

    Article  CAS  PubMed  Google Scholar 

  4. Hulsey M, Goldstein R, Scully L, Surbeck W, Reichlin M. Antiribosomal P antibodies in systemic lupus erythematosus: a case control study correlating hepatic and renal disease. Clin Immunol Immunopathol. 1995;74:252–6.

    Article  CAS  PubMed  Google Scholar 

  5. Koren E, Reichlin MW, Koscec M, Fugate RD, Reichlin M. Autoantibodies to the ribosomal P proteins react with a plasma membrane-related target on human cells. J Clin Invest. 1992;89:1236–41.

    Article  CAS  PubMed  Google Scholar 

  6. Hirohata S, Nakanishi K. Antiribosomal P protein antibody in human systemic lupus erythematosus reacts specifically with activated T cells. Lupus. 2001;10:612–21.

    Article  CAS  PubMed  Google Scholar 

  7. Nagai T, Arinuma Y, Yanagida T, Yamamoto K, Hirohata S. Anti-ribosomal P protein antibody in human systemic lupus erythematosus up-regulates the expression of proinflammatory cytokines by human peripheral blood monocytes. Arthritis Rheum. 2005;52:847–55.

    Article  CAS  PubMed  Google Scholar 

  8. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787–93.

    Article  CAS  PubMed  Google Scholar 

  9. Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997;15:297–322.

    Article  CAS  PubMed  Google Scholar 

  10. Lichtman AH, Abbas AK. T-cell subsets: recruiting the right kind of help. Curr Biol. 1997;7:R242–4.

    Article  CAS  PubMed  Google Scholar 

  11. Romagnani S. The Th1/Th2 paradigm. Immunol Today. 1997;18:263–6.

    Article  CAS  PubMed  Google Scholar 

  12. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–73.

    Article  CAS  PubMed  Google Scholar 

  13. Kamogawa Y, Minasi LA, Carding SR, Bottomly K, Flavell RA. The relationship of IL-4- and IFN gamma-producing T cells studied by lineage ablation of IL-4-producing cells. Cell. 1993;75:985–95.

    Article  CAS  PubMed  Google Scholar 

  14. Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991;146:3074–81.

    CAS  PubMed  Google Scholar 

  15. Trinchieri G. Interleukin-12 and its role in the generation of Th1 cells. Immunol Today. 1993;14:335–8.

    Article  CAS  PubMed  Google Scholar 

  16. Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, et al. Natural killer cell stimulatory factor (interleukin 12 [IL12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993;177:1199–204.

    Article  CAS  PubMed  Google Scholar 

  17. Schmitt E, Hoehn P, Germann T, Rüde E. Differential effects of interleukin-12 on the development of naive mouse CD4+ T cells. Eur J Immunol. 1994;24:343–7.

    Article  CAS  PubMed  Google Scholar 

  18. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–7.

    Article  CAS  PubMed  Google Scholar 

  19. Shibuya H, Nagai T, Ishii A, Yamamoto K, Hirohata S. Differential regulation of Th1 responses and CD154 expression in human CD4+ T cells by IFN-alpha. Clin Exp Immunol. 2003;132:216–24.

    Article  CAS  PubMed  Google Scholar 

  20. Shibuya H, Hirohata S. Differential effects of IFN-alpha on the expression of various TH2 cytokines in human CD4+ T cells. J Allergy Clin Immunol. 2005;116:205–12.

    Article  CAS  PubMed  Google Scholar 

  21. Hirohata S. Human Th1 responses driven by IL-12 are associated with enhanced expression of CD40 ligand. Clin Exp Immunol. 1999;115:78–85.

    Article  CAS  PubMed  Google Scholar 

  22. Collart MA, Baeuerle P, Vassalli P. Regulation of tumor necrosis factor α transcription in macrophages: involvement of four κB-like motifs and of constitutive and inducible forms of NF-κB. Mol Cell Biol. 1990;10:1498–506.

    CAS  PubMed  Google Scholar 

  23. Liu H, Sidiropoulos P, Song G, Pagliari LJ, Birrer MJ, Stein B, et al. TNF-α gene expression in macrophages: regulation by NF-κB is independent of c-Jun or C/EBP β. J Immunol. 2000;164:4277–85.

    CAS  PubMed  Google Scholar 

  24. Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K. Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol. 1990;10:561–8.

    CAS  PubMed  Google Scholar 

  25. Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990;10:2327–34.

    CAS  PubMed  Google Scholar 

  26. Zhang YH, Lin JX, Vilcek J. Interleukin-6 induction by tumor necrosis factor and interleukin-1 in human fibroblasts involves activation of a nuclear factor binding to a kappa B-like sequence. Mol Cell Biol. 1990;10:3818–23.

    CAS  PubMed  Google Scholar 

  27. Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM. Regulation of interleukin 12 p 40 expression through NF-kappa B half site. Mol Cell Biol. 1995;15:5258–67.

    CAS  PubMed  Google Scholar 

  28. Ma X, Chow JM, Gri G, Carra G, Gerosa F, Wolf SF, et al. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med. 1996;183:147–57.

    Article  CAS  PubMed  Google Scholar 

  29. Gri G, Savio D, Trinchieri G, Ma X. Synergistic regulation of the human interleukin-12 p40 promoter by NFkB and Ets transcription factors in Epstein–Barr virus transformed B cells and macrophages. J Biol Chem. 1998;273:6431–8.

    Article  CAS  PubMed  Google Scholar 

  30. Li X, Qin J. Modulation of Toll-interleukin 1 receptor mediated signaling. J Mol Med. 2005;83:258–66.

    Article  CAS  PubMed  Google Scholar 

  31. Hagiwara E, Gourley MF, Lee S, Klinman DK. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin 10: interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum. 1996;39:379–85.

    Article  CAS  PubMed  Google Scholar 

  32. Okada H, Konishi K, Nakazato Y, Kanno Y, Suzuki H, Sakaguchi H, et al. Interleukin-4 expression in mesangial proliferative glomerulonephritis. Am J Kidney Dis. 1994;23:242–6.

    CAS  PubMed  Google Scholar 

  33. Funauchi M, Ikoma S, Enomoto H, Horiuchi A. Decreased Th1-like and increased Th2-like cells in systemic lupus erythematosus. Scand J Rheumatol. 1998;27:219–24.

    Article  CAS  PubMed  Google Scholar 

  34. Al-Janadi M, Al-Balla S, Al-Dalaan A, Raziuddin S. Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic disease. J Clin Immunol. 1993;13:58–67.

    Article  CAS  PubMed  Google Scholar 

  35. Takahashi S, Fossati L, Iwamoto M, Merino R, Motta R, Kobayakawa T, et al. Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. J Clin Invest. 1996;97:1597–604.

    Article  CAS  PubMed  Google Scholar 

  36. Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, et al. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum. 1999;42:1644–8.

    Article  CAS  PubMed  Google Scholar 

  37. Tucci M, Lombardi L, Richards HB, DammaccoF Silvestris F. Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis. Clin Exp Immunol. 2008;154:247–54.

    Article  CAS  PubMed  Google Scholar 

  38. Schmidt-Weber CB, Akdis M, Akdis CA. TH17 cells in the big picture of immunology. J Allergy Clin Immunol. 2007;120:247–54.

    Article  CAS  PubMed  Google Scholar 

  39. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–67.

    Article  CAS  PubMed  Google Scholar 

  40. Takatori H, Kanno Y, Chen Z, O’Shea JJ. New complexities in helper T cell fate determination and the implications for autoimmune diseases. Mod Rheumatol. 2008;18:533–41.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang Z, Kyttaris VC, Tsokos GC. The role of IL-23/IL-17 axis in lupus nephritis. J Immunol. 2009;183:3160–9.

    Article  CAS  PubMed  Google Scholar 

  42. Jacob N, Yang H, Pricop L, Liu Y, Gao X, Zheng SG, et al. Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway. J Immunol. 2009;182:2532–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tatsuo Nagai.

About this article

Cite this article

Nagai, T., Yanagida, T. & Hirohata, S. Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes. Mod Rheumatol 21, 57–62 (2011). https://doi.org/10.1007/s10165-010-0354-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10165-010-0354-y

Keywords

Navigation