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Molecular Medicine

, Volume 12, Issue 11–12, pp 284–290 | Cite as

Morphine Reciprocally Regulates IL-10 and IL-12 Production by Monocyte-Derived Human Dendritic Cells and Enhances T Cell Activation

  • Davorka MessmerEmail author
  • Ikusuke Hatsukari
  • Naoko Hitosugi
  • Ingo G H Schmidt-Wolf
  • Pravin C Singhal
Research Article

Abstract

We evaluated the effect of morphine on human dendritic cells (DCs). Interestingly, immature DCs were found to express all 3 (μ, κ, δ) opioid receptors on the cell surface. Chronic morphine treatment (10−8 to 10−12 M) during the development of DCs from monocytes augmented LPS-induced upregulation of HLA-DR, CD86, CD80, and CD83 and increased the T cell stimulatory capacity of DCs, which could be inhibited by naloxone, an opioid receptor antagonist. The change in surface phenotype was paralleled by a p38 MAPK-dependent decrease in IL-10 and increase in IL-12 secretion. Our data indicate that morphine exerts an immunostimulatory effect by modulating LPS-induced DC maturation.

Notes

Acknowledgments

We wish to thank Gloria Telusma and Nick Franki for their technical assistance and Cathy Rapelje for FACS analysis. We also thank Ona Bloom for critical reading of the manuscript. This work was supported by grants (5RO1DA12111) from the National Institutes of Health.

References

  1. 1.
    Rouveix B. (1992) Opiates and immune function: consequences on infectious diseases with special reference to AIDS. Therapie 47:503–12.PubMedGoogle Scholar
  2. 2.
    Sibinga NE, Goldstein A. (1988) Opioid peptides and opioid receptors in cells of the immune system. Annu. Rev. Immunol. 6:219–49.CrossRefGoogle Scholar
  3. 3.
    Weigent DA, Blalock JE. (1987) Interactions between the neuroendocrine and immune systems: common hormones and receptors. Immunol. Rev. 100:79–108.CrossRefGoogle Scholar
  4. 4.
    Vallejo R, de Leon-Casasola O, Benyamin R. (2004) Opioid therapy and immunosuppression: a review. Am. J. Ther. 11:354–65.CrossRefGoogle Scholar
  5. 5.
    Roy S, Loh HH. (1996) Effects of opioids on the immune system. Neurochem. Res. 21:1375–86.CrossRefGoogle Scholar
  6. 6.
    Eisenstein TK, Hilburger ME. (1998) Opioid modulation of immune responses: effects on phagocyte and lymphoid cell populations. J. Neuroimmunol. 83:36–44.CrossRefGoogle Scholar
  7. 7.
    Bryant HU, Bernton EW, Holaday JW. (1987) Immunosuppressive effects of chronic morphine treatment in mice. Life Sci. 41:1731–8.CrossRefGoogle Scholar
  8. 8.
    Liang-Suo J, Gomez-Flores R, Weber RJ. (2002) Immunosuppression induced by central action of morphine is not blocked by mifepristone (RU 486). Life Sci. 71:2595–602.CrossRefGoogle Scholar
  9. 9.
    Luza J. (1992) Effect of morphine on phagocytic activity of the polymorphonuclears and monocytes. Acta Univ. Palacki Olomuc. Fac. Med. 134:47–50.PubMedGoogle Scholar
  10. 10.
    Liu Y, Blackbourn DJ, Chuang LF, Killam KFJr, Chuang RY. (1992) Effects of in vivo and in vitro administration of morphine sulfate upon rhesus macaque polymorphonuclear cell phagocytosis and chemotaxis. J. Pharmacol. Exp. Ther. 263:533–9.PubMedGoogle Scholar
  11. 11.
    Donahoe RM, et al. (2001) Effects of morphine on T-cell recirculation in rhesus monkeys. Adv. Exp. Med. Biol. 493:89–101.CrossRefGoogle Scholar
  12. 12.
    Bryant HU, Bernton EW, Holaday JW. (1988) Morphine pellet-induced immunomodulation in mice: temporal relationships. J. Pharmacol. Exp. Ther. 245:913–20.PubMedGoogle Scholar
  13. 13.
    Singhal P, Kapasi A, Reddy K, Franki N. (2001) Opiates promote T cell apoptosis through JNK and caspase pathway. Adv. Exp. Med. Biol. 493:127–35.CrossRefGoogle Scholar
  14. 14.
    Bhat RS, Bhaskaran M, Mongia A, Hitosugi N, Singhal PC. (2004) Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation. J. Leukoc. Biol. 75:1131–8.CrossRefGoogle Scholar
  15. 15.
    Malik AA, Radhakrishnan N, Reddy K, Smith AD, Singhal PC. (2002) Morphine-induced macrophage apoptosis modulates migration of macrophages: use of in vitro model of urinary tract infection. J. Endourol. 16:605–10.CrossRefGoogle Scholar
  16. 16.
    Bhaskaran M, et al. (2001) Morphine-induced degradation of the host defense barrier: role of macrophage injury. J. Infect. Dis. 184:1524–31.CrossRefGoogle Scholar
  17. 17.
    Singhal PC, Sharma P, Kapasi AA, Reddy K, Franki N, Gibbons N. (1998) Morphine enhances macrophage apoptosis. J. Immunol. 160:1886–93.PubMedGoogle Scholar
  18. 18.
    Gomez-Flores R, Suo JL, Weber RJ. (1999) Suppression of splenic macrophage functions following acute morphine action in the rat mesencephalon periaqueductal gray. Brain Behav. Immun. 13:212–24.CrossRefGoogle Scholar
  19. 19.
    Roy S, Charboneau RG, Barke RA. (1999) Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model. J. Neuroimmunol. 95:107–14.CrossRefGoogle Scholar
  20. 20.
    Eisenstein TK, Rogers TJ, Meissler JJ Jr, Adler MW, Hilburger ME. (1998) Morphine depresses macrophage numbers and function in mouse spleens. Adv. Exp. Med. Biol. 437:33–41.CrossRefGoogle Scholar
  21. 21.
    Banchereau J, Steinman RM. (1998) Dendritic cells and the control of immunity. Nature 392:245–52.CrossRefGoogle Scholar
  22. 22.
    Asahina A, Hosoi J, Grabbe S, Granstein RD. (1995) Modulation of Langerhans cell function by epidermal nerves. J. Allergy Clin. Immunol. 96:1178–82.CrossRefGoogle Scholar
  23. 23.
    Asahina A, et al. (1995) Specific induction of cAMP in Langerhans cells by calcitonin generelated peptide: relevance to functional effects. Proc. Natl. Acad. Sci. U. S. A. 92:8323–7.CrossRefGoogle Scholar
  24. 24.
    Marriott I, Mason MJ, Elhofy A, Bost KL. (2000) Substance P activates NF-kappaB independent of elevations in intracellular calcium in murine macrophages and dendritic cells. J. Neuroimmunol. 102:163–71.CrossRefGoogle Scholar
  25. 25.
    Delneste Y, et al. (1999) Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation. J. Immunol. 163:3071–5.PubMedGoogle Scholar
  26. 26.
    Kirst A, Wack C, Lutz WK, Eggert A, Kampgen E, Fischer WH. (2002) Expression of functional kappa-opioid receptors on murine dendritic cells. Immunol. Lett. 84:41–8.CrossRefGoogle Scholar
  27. 27.
    Makarenkova VP, et al. (2001) Identification of delta- and mu-type opioid receptors on human and murine dendritic cells. J. Neuroimmunol. 117:68–77.CrossRefGoogle Scholar
  28. 28.
    Reisine T, Brownstein MJ. (1994) Opioid and cannabinoid receptors. Curr. Opin. Neurobiol. 4:406–12.CrossRefGoogle Scholar
  29. 29.
    Taga K, Tosato G. (1992) IL-10 inhibits human T cell proliferation and IL-2 production. J. Immunol. 148:1143–8.PubMedGoogle Scholar
  30. 30.
    Esche C, et al. (1999) Murine dendritic cells express functional delta-type opioid receptors. Ann. N. Y. Acad. Sci. 885:387–90.CrossRefGoogle Scholar
  31. 31.
    Gilliet M, et al. (2002) The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 195:953–8.CrossRefGoogle Scholar
  32. 32.
    Basu S, Srivastava P. (2005) Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells. Proc. Natl. Acad. Sci. U. S. A. 102:5120–5.CrossRefGoogle Scholar
  33. 33.
    McBride JM, Jung T, de Vries JE, Aversa G. (2002) IL-10 alters DC function via modulation of cell surface molecules resulting in impaired T-cell responses. Cell Immunol. 215:162–72.CrossRefGoogle Scholar
  34. 34.
    Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G. (2001) Regulatory activity of autocrine IL-10 on dendritic cell functions. J. Immunol. 166:4312–8.CrossRefGoogle Scholar
  35. 35.
    Xia CQ, Kao KJ. (2003) Suppression of interleukin-12 production through endogenously secreted interleukin-10 in activated dendritic cells: involvement of activation of extracellular signal-regulated protein kinase. Scand. J. Immunol. 58, 23–32.CrossRefGoogle Scholar
  36. 36.
    Trinchieri G. (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13:251–76.CrossRefGoogle Scholar
  37. 37.
    Peng X, Mosser DM, Adler MW, Rogers TJ, Meissler JJ Jr, Eisenstein TK. (2000) Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages. J. Leukoc. Biol. 68:723–8.PubMedGoogle Scholar
  38. 38.
    Zurawski G, Benedik M, Kamb BJ, Abrams JS, Zurawski SM, Lee FD. (1986) Activation of mouse T-helper cells induces abundant preproenkephalin mRNA synthesis. Science 232:772–5.CrossRefGoogle Scholar
  39. 39.
    Linner KM, Quist HE, Sharp BM. (1995) Metenkephalin-containing peptides encoded by proenkephalin A mRNA expressed in activated murine thymocytes inhibit thymocyte proliferation. J. Immunol. 154:5049–60.PubMedGoogle Scholar
  40. 40.
    Cabot PJ, Carter L, Schafer M, Stein C. (2001) Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. Pain 93:207–12.CrossRefGoogle Scholar
  41. 41.
    Gately MK, et al. (1998) The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu. Rev. Immunol. 16:495–521.CrossRefGoogle Scholar
  42. 42.
    Ulevitch RJ, Tobias PS. (1995) Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13:437–57.CrossRefGoogle Scholar
  43. 43.
    Falcone M, Sarvetnick N. (1999) Cytokines that regulate autoimmune responses. Curr. Opin. Immunol. 11:670–6.CrossRefGoogle Scholar
  44. 44.
    Li W, et al. (2001) Il-12 antagonism enhances apoptotic death of T cells within hepatic allografts from Flt3 ligand-treated donors and promotes graft acceptance. J. Immunol. 166:5619–28.CrossRefGoogle Scholar
  45. 45.
    Finkelman FD, et al. (1997) Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models. Annu. Rev. Immunol. 15:505–33.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2006

Authors and Affiliations

  • Davorka Messmer
    • 1
    Email author
  • Ikusuke Hatsukari
    • 2
  • Naoko Hitosugi
    • 2
  • Ingo G H Schmidt-Wolf
    • 3
  • Pravin C Singhal
    • 2
  1. 1.Laboratory of Experimental ImmunologyThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.The Division of Kidney Diseases and HypertensionLong Island Jewish Medical CenterNew Hyde ParkUSA
  3. 3.Department of Internal MedicineRheinische Friedrich-Wilhelms UniversitaetBonnGermany

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