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The Opioidergic System of Immune Cells: A New Pharmacological Target in the Therapy of “Cytokine Storm”

https://doi.org/10.33647/2074-5982-16-4-14-23

Abstract

This article proposes a new pharmacological approach to suppressing “cytokine storm” syndromes based on the use of opioid peptides. Immune cells possess a complete opioid signaling system consisting of all three types of opioid receptors: mu (μ), delta (δ) and kappa (κ). These cells also express proopiomelanocortin, proenkephalin and prodinorphin, which serve as precursors for such receptor agonists as β-endorphin, methenkephalin and dynorphins, respectively. A distinct feature of the opioid system of immunocytes consists in an increased expression of all its components in response to the action of cytokines and inflammation, which indicates participation of this system in regulating the immune response. It has been recently shown that dynorphins are likely to play an important role in inhibiting the expression of proinflammatory cytokines by immune cells through impeding the translocation of the active nuclear factor kappa B (NF-κB) dimer. Given the key role of the canonical pathway of NF-κB activation in cytokine expression realized when activating a variety of receptors, suppression of this pathway using opioid peptides provides a new pharmacological approach to solving the “cytokine storm” problem. The relevance of this approach is associated with the COVID-19 coronavirus infection pandemic, the role of the “cytokine storm” in which has been established by numerous studies.

About the Authors

V. N. Karkischenko
Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia
Russian Federation

Vladislav N. Karkischenko, Dr. Sci. (Med.), Prof.

143442, Moscow region, Krasnogorsk district, Svetlye gory village, building 1



I. A. Pomytkin
Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia
Russian Federation

Igor A. Pomytkin, Cand. Sci. (Chem.)

143442, Moscow region, Krasnogorsk district, Svetlye gory village, building 1



V. I. Skvortsova
Federal Medical and Biological Agency of Russia
Russian Federation

Veronika I. Skvortsova, Dr. Sci. (Med.), Prof., Corresponding Member of the Russian Academy of Sciences

123182, Moscow, Volokolamskoye highway, 30



References

1. Karkischenko N.N. Al’ternativy biomeditsiny. T. 1. Osnovy biomeditsiny i farmako-modelirovaniya [Biomedicine alternatives. Vol. 1. Fundamentals of biomedicine and pharmaco-modeling]. Moscow: Izdatel’stvo VPK, 2007, 320 p. (In Russian).

2. Cabot P.J., Carter L., Gaiddon C., Zhang Q., Schäfer M., Loeffler J.P., et al. Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. J. Clin. Invest. 1997;100(1):142–148. DOI: 10.1172/JCI119506.

3. Cabot P.J., Carter L., Schäfer M., Stein C. Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. Pain. 2001;93(3):207–212. DOI: 10.1016/s03043959(01)00322-0.

4. Cabot P.J. Immune-derived opioids and peripheral antinociception. Clin. Exp. Pharmacol. Physiol. 2001;28(3):230–232. DOI: 10.1046/j.1440-1681.2001.03425.x.

5. Chen Y.L., Law P.Y., Loh H.H. Action of NF-kappaB on the delta opioid receptor gene promoter. Biochem. Biophys. Res. Commun. 2007;352(3):818–822. DOI: 10.1016/j.bbrc.2006.11.103.

6. Chen Y.L., Law P.Y., Loh H.H. Nuclear factor kappaB signaling in opioid functions and receptor gene expression. J. Neuroimmune Pharmacol. 2006;1(3):270–279. DOI: 10.1007/s11481-006-9028-0.

7. Chen Y.L., Law P.Y., Loh H.H. Sustained activation of phosphatidylinositol 3-kinase/Akt/nuclear factor kappaB signaling mediates G protein-coupled delta-opioid receptor gene expression. J. Biol. Chem. 2006;281(6):3067–3074.

8. Członkowski A., Stein C., Herz A. Peripheral mechanisms of opioid antinociception in inflammation: involvement of cytokines. Eur. J. Pharmacol. 1993;242(3):229–235. DOI: 10.1016/0014-2999(93)90246-e.

9. Fazalul Rahiman S.S., Morgan M., Gray P., Shaw P.N., Cabot P.J. Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells. PLoS One. 2016;11(4):e0153005. DOI: 10.1371/journal.pone.0153005.

10. Gao Y.M., Xu G., Wang B., Liu B.C. Cytokine storm syndrome in coronavirus disease 2019: A narrative review. J. Intern. Med. 2020. DOI: 10.1111/joim.13144.

11. Hassan A.H., Pzewłocki R., Herz A., Stein C. Dynorphin, a preferential ligand for kappa-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat. Neurosci. Lett. 1992;140(1):85–88. DOI: 10.1016/0304-3940(92)90688-4.

12. Henry B.M., de Oliveira M.H.S., Benoit S., Plebani M., Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin. Chem. Lab. Med. 2020;58(7):10211028. DOI: 10.1515/cclm-2020-0369.

13. Jiménez N., Puig M.M., Pol O. Antiexudative effects of opioids and expression of kappa- and delta-opioid receptors during intestinal inflammation in mice: involvement of nitric oxide. J. Pharmacol. Exp. Ther. 2006;316(1):261–270. DOI: 10.1124/jpet.105.091991.

14. Kraus J., Börner C., Giannini E., Höllt V. The role of nuclear factor kappaB in tumor necrosis factor-regulated transcription of the human mu-opioid receptor gene. Mol. Pharmacol. 2003; 64(4):876–884.

15. Law P.Y., Loh H.H., Wei L.N. Insights into the receptor transcription and signaling: implications in opioid tolerance and dependence. Neuropharmacology. 2004;47(1):300–311.

16. Liu T., Zhang L., Joo D., Sun S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2017;2. DOI: 10.1038/sigtrans.2017.23.

17. Lolait S.J., Clements J.A., Markwick A.J., Cheng C., McNally M., Smith A.I., et al. Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta endorphin in spleen macrophages. J. Clin. Invest. 1986;77(6):1776–1779. DOI: 10.1172/JCI112501.

18. Mitchell S., Vargas J., Hoffmann A. Signaling via the NFκB system. Wiley Interdiscip. Rev. Syst. Biol. Med. 2016;8(3):227–241. DOI: 10.1002/wsbm.1331.

19. Morgan M., Heffernan A., Benhabib F., Wagner S., Hewavitharana A.K., Shaw P.N., et al. The efficacy of Dynorphin fragments at the κ, μ and δ opioid receptor in transfected HEK cells and in an animal model of unilateral peripheral inflammation. Peptides. 2017;89:9–16. DOI: 10.1016/j.peptides.2016.12.019.

20. Morgan M., Herath H.M., Cabot P.J., Shaw P.N., Hewavitharana A.K. Dynorphin A 1-17 biotransformation in inflamed tissue, serum and trypsin solution analysed by liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 2012;404(10):31113121. DOI: 10.1007/s00216-012-6406-8.

21. Peterson P.K., Molitor T.W., Chao C.C. The opioid-cytokine connection. J. Neuroimmunol. 1998;83(1–2):63–69. DOI: 10.1016/s0165-5728(97)00222-1.

22. Philippe D., Chakass D., Thuru X., Zerbib P., Tsicopoulos A., Geboes K., et al. Mu opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation. Gut. 2006;55(6):815–823. DOI: 10.1136/gut.2005.080887.

23. Pol O., Alameda F., Puig M.M. Inflammation enhances mu-opioid receptor transcription and expression in mice intestine. Mol. Pharmacol. 2001;60(5):894–899. DOI: 10.1124/mol.60.5.894.

24. Pol O., Palacio J.R., Puig M.M. The expression of delta- and kappa-opioid receptor is enhanced during intestinal inflammation in mice. J. Pharmacol. Exp. Ther. 2003;306(2):455–462. DOI: 10.1124/jpet.103.049346.

25. Przewłocki R., Hassan A.H., Lason W., Epplen C., Herz A., Stein C. Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception. Neuroscience. 1992;48(2):491–500. DOI: 10.1016/0306-4522(92)90509-z.

26. Schäfer M., Carter L., Stein C. Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proc. Natl Acad. Sci. USA. 1994;91(10):4219–4223. DOI: 10.1073/pnas.91.10.4219.

27. Sharp B.M. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behav. Immun. 2006;20(1):9–14. DOI: 10.1016/j.bbi.2005.02.00.

28. Smith E.M., Morrill A.C., Meyer W.J. 3rd, Blalock J.E. Corticotropin releasing factor induction of leukocyte-derived immunoreactive ACTH and endorphins. Nature. 1986;321(6073):881–882. DOI: 10.1038/321881a0.

29. Stefano G.B., Scharrer B., Smith E.M., Hughes T.K. Jr., Magazine H.I., Bilfinger T.V., et al. Opioid and Opiate Immunoregulatory Processes. Crit. Rev. Immunol. 2017;37(2–6):213–248. DOI: 10.1615/CritRevImmunol.v37.i2-6.40.

30. Stein C., Hassan A.H., Przewłocki R., Gramsch C., Peter K., Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc. Natl Acad. Sci. USA. 1990;87(15):5935–5939. DOI: 10.1073/pnas.87.15.5935.

31. Wybran J., Appelboom T., Famaey J.P., Govaerts A. Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J. Immunol. 1979;123(3):1068–1070.

32. Zurawski G., Benedik M., Kamb B.J., Abrams J.S., Zurawski S.M., Lee F.D. Activation of mouse T-helper cells induces abundant preproenkephalin mRNA synthesis. Science. 1986;232(4751):772–775. DOI: 10.1126/science.2938259.


Review

For citations:


Karkischenko V.N., Pomytkin I.A., Skvortsova V.I. The Opioidergic System of Immune Cells: A New Pharmacological Target in the Therapy of “Cytokine Storm”. Journal Biomed. 2020;16(4):14-23. (In Russ.) https://doi.org/10.33647/2074-5982-16-4-14-23

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