Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-24T00:22:27.067Z Has data issue: false hasContentIssue false
  • English
  • Français

Morphine inhibits AP-1 activity and CD14 expression in leukocytes by a nitric oxide and opioid receptor-dependent mechanism

Published online by Cambridge University Press:  01 November 2007

I. D. Welters ,
A. Menzebach ,
Y. Goumon ,
T. W. Langefeld ,
H. Harbach ,
J. Mühling ,
P. Cadet  and
G. B. Stefano
I. D. Welters*
Affiliation:
University of Liverpool, Division of Clinical Sciences, Liverpool, UK Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
A. Menzebach
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany Klinik und Poliklinik für Anaesthesie und Intensivtherapie der Universität Rostock, Germany
Y. Goumon
Affiliation:
INSERM 575, IFR 37, ‘Physiopathology of the Nervous System’, Strasbourg Cedex, France
T. W. Langefeld
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
H. Harbach
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
J. Mühling
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
P. Cadet
Affiliation:
State University of New York at Old Westbury, Neuroscience Research Institute, Old Westbury, NY, USA
G. B. Stefano
Affiliation:
State University of New York at Old Westbury, Neuroscience Research Institute, Old Westbury, NY, USA
*
Correspondence to: Ingeborg D. Welters, School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool L69 3GA, UK. E-mail: [email protected]; Tel: +44 151 706 4003; Fax:+44 151 706 5884
Get access

Summary

Background

Activator protein 1 is a transcription factor involved in the regulation of proinflammatory mediators. Activation of phagocytes by lipopolysaccharide depends on the expression of CD14 on the cell surface. In this study, we investigated the effects of morphine and nitric oxide on CD14 expression and activator protein 1 activation in human blood monocytes and neutrophils as well as the leukocyte cell line HL-60.

Methods

Whole blood was incubated with morphine, the nitric oxide donor S-nitroso-N-acetyl-penicillamine, naloxone or nitric oxide synthase inhibitors Nω-nitro-l-arginine and Nω-nitro-l-arginine-methylester and stimulated with lipopolysaccharide. Activator protein 1 nuclear content was determined by flow cytometry in human blood neutrophils and monocytes. CD14 expression on neutrophils was measured after incubation with fluorescein isothiocyanate-labelled antibodies. Electric mobility shift assay served for evaluation of activator protein 1 nuclear binding in HL-60 cells.

Results

Incubation of whole blood with morphine and subsequent stimulation with lipopolysaccharide decreased activator protein 1 nuclear content. Exposure to naloxone before morphine treatment abolished morphine-induced inhibition of activator protein 1 activity in human blood monocytes and neutrophils. Nitric oxide synthase inhibitors also reversed morphine’s effects. CD14 expression on neutrophils was reduced after morphine treatment. These effects were antagonized by nitric oxide synthase inhibitors and naloxone.

Conclusion

Morphine inhibits activator protein 1 activation by a μ opioid receptor pathway coupled to nitric oxide as second messenger. The decrease in CD14 expression caused by morphine may play a role in inhibition of activator protein 1 activation following lipopolysaccharide treatment of phagocytes.

Keywords

MORPHINENITRIC OXIDEOPIOID RECEPTORSTRANSCRIPTION FACTOR AP-1LIPOPOLYSCCHARIDEL-SELECTINLEUKOCYTES
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 11 , November 2007 , pp. 958 - 965
Copyright
Copyright © European Society of Anaesthesiology 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Welters, ID, Menzebach, A, Goumon, Y et al. . Morphine suppresses complement receptor expression, phagocytosis, and respiratory burst in neutrophils by a nitric oxide and μ3 opiate receptor-dependent mechanism. J Neuroimmunol 2000; 111: 139–145.Google Scholar
2.Stefano, GB, Scharrer, B, Smith, EM et al. . Opioid and opiate immunoregulatory processes. Crit Rev Immunol 1996; 16: 109–144.Google Scholar
3.Welters, ID, Menzebach, A, Goumon, Y et al. . Morphine inhibits NF-κB nuclear binding in human neutrophils and monocytes by a nitric oxide dependent mechanism. Anesthesiology 2000; 92: 1677–1684.CrossRefGoogle ScholarPubMed
4.Cadet, P, Mantione, KJ, Stefano, GB. Molecular identification and functional expression of mu 3, a novel alternatively spliced variant of the human mu opiate receptor gene. J Immunol 2003; 170: 5118–5123.CrossRefGoogle ScholarPubMed
5.Chuang, TK, Killam, KFJ, Chuang, LF et al. . Mu opioid receptor gene expression in immune cells. Biochem Biophys Res Commun 1995; 216: 922–930.CrossRefGoogle ScholarPubMed
6.Magazine, HI, Liu, Y, Bilfinger, TV, Fricchione, GL, Stefano, GB. Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide. J Immunol 1996; 156: 4845–4850.CrossRefGoogle ScholarPubMed
7.Van Amersfoort, ES, Van Berkel, TJ, Kuiper, J. Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev 2003; 16: 379–414.CrossRefGoogle ScholarPubMed
8.Triantafilou, M, Triantafilou, K. The dynamics of LPS recognition: complex orchestration of multiple receptors. J Endotoxin Res 2005; 11: 5–11.Google ScholarPubMed
9.Foletta, VC, Segal, DH, Cohen, DR. Transcriptional regulation in the immune system: all roads lead to AP-1. J Leukoc Biol 1998; 63: 139–152.CrossRefGoogle ScholarPubMed
10.Makman, MH, Dobrenis, K, Surratt, CK. Properties of mu 3 opiate alkaloid receptors in macrophages, astrocytes, and HL-60 human promyelocytic leukemia cells. Adv Exp Med Biol 1998; 437: 137–148.CrossRefGoogle ScholarPubMed
11.Foulds, S. Novel flow cytometric method for quantifying nuclear binding of the transcription factor nuclear factor kappa B in unseparated human monocytes and polymorphonuclear cells. Cytometry 1997; 29: 182–186.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
12.Schreiber, E, Matthias, P, Müller, MM, Schaffner, W. Rapid detection of octamer binding proteins with mini-extracts prepared from a small number of cells. Nucleic Acids Res 1989; 17: 6419.CrossRefGoogle ScholarPubMed
13.Cadet, P, Bilfinger, TV, Fimiani, C, Peter, D, Stefano, GB. Human vascular and cardiac endothelia express mu opiate receptor transcripts. Endothelium 2000; 7: 185–191.CrossRefGoogle ScholarPubMed
14.Menzebach, A, Hirsch, J, Nost, R, Mogk, M, Hempelmann, G, Welters, ID. Morphine inhibits complement receptor expression, phagocytosis and oxidative burst by a nitric oxide dependent mechanism. Anasthesiol Intensivmed Notfallmed Schmerzther 2004; 39: 204–211.Google Scholar
15.Ocasio, FM, Jiang, Y, House, SD, Chang, SL. Chronic morphine accelerates the progression of lipopolysaccharide-induced sepsis to septic shock. J Neuroimmunol 2004; 149: 90–100.Google Scholar
16.Perera, PY, Mayadas, TN, Takeuchi, O et al. . CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol 2001; 166: 574–581.Google Scholar
17.Roy, S, Chapin, RB, Cain, KJ, Charboneau, RG, Ramakrishnan, S, Barke, RA. Morphine inhibits transcriptional activation of IL-2 in mouse thymocytes. Cell Immunol 1997; 179: 1–9.CrossRefGoogle ScholarPubMed
18.Adcock, IM. Transcription factors as activators of gene transcription: AP-1 and NF kappa B. Monaldi Arch Chest Dis 1997; 52: 178–186.Google ScholarPubMed
19.Matthews, JR, Botting, CH, Panico, M, Morris, HR, Hay, RT. Inhibition of NF-kappaB DNA binding by nitric oxide. Nucl Acids Res 1996; 24: 2236–2242.Google Scholar
20.Nikitovic, D, Holmgren, A, Spyrou, G. Inhibition of AP-1 DNA binding by nitric oxide involving conserved cysteine residues in Jun and Fos. Biochem Biophys Res Commun 1998; 242: 109–112.CrossRefGoogle Scholar
21.Beck, M, Mirmohammadsadegh, A, Franz, B, Blanke, J, Hengge, UR. Opioid receptors on white blood cells: effect of HIV infection and methadone treatment. Pain 2002; 98: 187–194.CrossRefGoogle ScholarPubMed
22.Kraus, J, Borner, C, Giannini, E et al. . Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site. J Biol Chem 2001; 276: 43901–43908.CrossRefGoogle ScholarPubMed
23.Stefano, GB, Burrill, JD, Labur, S, Blake, J, Cadet, P. Regulation of various genes in human leukocytes acutely exposed to morphine: expression microarray analysis. Med Sci Monit 2005; 11: MS35–MS42.Google ScholarPubMed
24.Liebermann, DA, Gregory, B, Hoffman, B. AP-1 (Fos/Jun) transcription factors in hematopoietic differentiation and apoptosis. Int J Oncol 1998; 12: 685–700.Google ScholarPubMed
25.Singhal, PC, Sharma, P, Kapasi, AA, Reddy, K, Franki, N, Gibbons, N. Morphine enhances macrophage apoptosis. J Immunol 1998; 160: 1886–1893.CrossRefGoogle ScholarPubMed
26.Suzuki, S, Chuang, LF, Doi, RH, Chuang, RY. Morphine suppresses lymphocyte apoptosis by blocking p53-mediated death signaling. Biochem Biophys Res Commun 2003; 308: 802–808.CrossRefGoogle ScholarPubMed
27.Singhal, PC, Reddy, K, Franki, N, Sanwal, V, Gibbons, N. Morphine induces splenocyte apoptosis and enhanced mRNA expression of cathepsin-B. Inflammation 1997; 21: 609–617.Google Scholar