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. 1997 Aug;91(4):548–552. doi: 10.1046/j.1365-2567.1997.00285.x

The effects of dexamethasone and chlorpromazine on tumour necrosis factor-alpha, interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-10 in human volunteers.

M W Bleeker 1, M G Netea 1, B J Kullberg 1, J Van der Ven-Jongekrijg 1, J W Van der Meer 1
PMCID: PMC1363874  PMID: 9378493

Abstract

Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that play an important role in severe infections, whereas IL-1 receptor antagonist (IL-1ra) and IL-10 are anti-inflammatory cytokines that counteract their effects. Chlorpromazine and dexamethasone protect mice against lethal endotoxaemia by decreasing circulating concentrations of TNF-alpha and IL-1 beta. We investigated whether administration of chlorpromazine or dexamethasone to human volunteers is able to modulate the lipopolysaccharide (LPS)-stimulated cytokine production capacity in whole blood. Blood samples were taken before and several time-points after medication. Circulating cytokine concentrations were low in all samples. LPS-induced TNF-alpha and IL-1 beta production in whole blood was inhibited by dexamethasone treatment, while chlorpromazine had no effect. When peripheral blood mononuclear cells were stimulated in vitro with LPS, the addition of chlorpromazine (1-100 ng/ml) had no modulatory action on TNF-alpha, IL-1 beta, IL-1ra or IL-10 synthesis. The chlorpromazine concentrations measured in circulation of volunteers were eight to 40 times lower than the concentrations shown to be effective in mice. In conclusion, chlorpromazine inhibits TNF-alpha and IL-1 beta production in mice at concentrations that cannot be reached in humans, thus precluding its usage in clinical anti-cytokine strategies. In contrast, dexamethasone is an effective inhibitor of pro-inflammatory cytokine production.

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Selected References

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  1. Barber A. E., Coyle S. M., Fischer E., Smith C., van der Poll T., Shires G. T., Lowry S. F. Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings. Surgery. 1995 Aug;118(2):406–411. doi: 10.1016/s0039-6060(05)80352-6. [DOI] [PubMed] [Google Scholar]
  2. Barber A. E., Coyle S. M., Marano M. A., Fischer E., Calvano S. E., Fong Y., Moldawer L. L., Lowry S. F. Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man. J Immunol. 1993 Mar 1;150(5):1999–2006. [PubMed] [Google Scholar]
  3. Bertini R., Bianchi M., Ghezzi P. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med. 1988 May 1;167(5):1708–1712. doi: 10.1084/jem.167.5.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bertini R., Garattini S., Delgado R., Ghezzi P. Pharmacological activities of chlorpromazine involved in the inhibition of tumour necrosis factor production in vivo in mice. Immunology. 1993 Jun;79(2):217–219. [PMC free article] [PubMed] [Google Scholar]
  5. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  6. Drenth J. P., Van Uum S. H., Van Deuren M., Pesman G. J., Van der Ven-Jongekrijg J., Van der Meer J. W. Endurance run increases circulating IL-6 and IL-1ra but downregulates ex vivo TNF-alpha and IL-1 beta production. J Appl Physiol (1985) 1995 Nov;79(5):1497–1503. doi: 10.1152/jappl.1995.79.5.1497. [DOI] [PubMed] [Google Scholar]
  7. Endres S., Ghorbani R., Lonnemann G., van der Meer J. W., Dinarello C. A. Measurement of immunoreactive interleukin-1 beta from human mononuclear cells: optimization of recovery, intrasubject consistency, and comparison with interleukin-1 alpha and tumor necrosis factor. Clin Immunol Immunopathol. 1988 Dec;49(3):424–438. doi: 10.1016/0090-1229(88)90130-4. [DOI] [PubMed] [Google Scholar]
  8. Gadina M., Bertini R., Mengozzi M., Zandalasini M., Mantovani A., Ghezzi P. Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J Exp Med. 1991 Jun 1;173(6):1305–1310. doi: 10.1084/jem.173.6.1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gatti S., Faggioni R., Echtenacher B., Ghezzi P. Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality. Clin Exp Immunol. 1993 Mar;91(3):456–461. doi: 10.1111/j.1365-2249.1993.tb05924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kern J. A., Lamb R. J., Reed J. C., Daniele R. P., Nowell P. C. Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms. J Clin Invest. 1988 Jan;81(1):237–244. doi: 10.1172/JCI113301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Martinez F., Coleman J. W. The effects of selected drugs, including chlorpromazine and non-steroidal anti-inflammatory agents, on polyclonal IgG synthesis and interleukin 1 production by human peripheral blood mononuclear cells in vitro. Clin Exp Immunol. 1989 May;76(2):252–257. [PMC free article] [PubMed] [Google Scholar]
  12. Mengozzi M., Fantuzzi G., Faggioni R., Marchant A., Goldman M., Orencole S., Clark B. D., Sironi M., Benigni F., Ghezzi P. Chlorpromazine specifically inhibits peripheral and brain TNF production, and up-regulates IL-10 production, in mice. Immunology. 1994 Jun;82(2):207–210. [PMC free article] [PubMed] [Google Scholar]
  13. Netea M. G., Blok W. L., Kullberg B. J., Bemelmans M., Vogels M. T., Buurman W. A., van der Meer J. W. Pharmacologic inhibitors of tumor necrosis factor production exert differential effects in lethal endotoxemia and in infection with live microorganisms in mice. J Infect Dis. 1995 Feb;171(2):393–399. doi: 10.1093/infdis/171.2.393. [DOI] [PubMed] [Google Scholar]
  14. Parrillo J. E. Pathogenetic mechanisms of septic shock. N Engl J Med. 1993 May 20;328(20):1471–1477. doi: 10.1056/NEJM199305203282008. [DOI] [PubMed] [Google Scholar]
  15. Santos A. A., Scheltinga M. R., Lynch E., Brown E. F., Lawton P., Chambers E., Browning J., Dinarello C. A., Wolff S. M., Wilmore D. W. Elaboration of interleukin 1-receptor antagonist is not attenuated by glucocorticoids after endotoxemia. Arch Surg. 1993 Feb;128(2):138–144. doi: 10.1001/archsurg.1993.01420140015003. [DOI] [PubMed] [Google Scholar]
  16. Sauer J., Castren M., Hopfner U., Holsboer F., Stalla G. K., Arzt E. Inhibition of lipopolysaccharide-induced monocyte interleukin-1 receptor antagonist synthesis by cortisol: involvement of the mineralocorticoid receptor. J Clin Endocrinol Metab. 1996 Jan;81(1):73–79. doi: 10.1210/jcem.81.1.8550797. [DOI] [PubMed] [Google Scholar]
  17. Scheinman R. I., Cogswell P. C., Lofquist A. K., Baldwin A. S., Jr Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995 Oct 13;270(5234):283–286. doi: 10.1126/science.270.5234.283. [DOI] [PubMed] [Google Scholar]
  18. Schleuning M. J., Duggan A., Reem G. H. Inhibition by chlorpromazine of lymphokine-specific mRNA expression in human thymocytes. Eur J Immunol. 1989 Aug;19(8):1491–1495. doi: 10.1002/eji.1830190822. [DOI] [PubMed] [Google Scholar]
  19. Tarazona R., González-García A., Zamzami N., Marchetti P., Frechin N., Gonzalo J. A., Ruiz-Gayo M., van Rooijen N., Martínez C., Kroemer G. Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo. J Immunol. 1995 Jan 15;154(2):861–870. [PubMed] [Google Scholar]
  20. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  21. Waage A., Bakke O. Glucocorticoids suppress the production of tumour necrosis factor by lipopolysaccharide-stimulated human monocytes. Immunology. 1988 Feb;63(2):299–302. [PMC free article] [PubMed] [Google Scholar]
  22. Wakabayashi G., Gelfand J. A., Burke J. F., Thompson R. C., Dinarello C. A. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J. 1991 Mar 1;5(3):338–343. doi: 10.1096/fasebj.5.3.1825816. [DOI] [PubMed] [Google Scholar]
  23. Zinetti M., Galli G., Demitri M. T., Fantuzzi G., Minto M., Ghezzi P., Alzani R., Cozzi E., Fratelli M. Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro. Immunology. 1995 Nov;86(3):416–421. [PMC free article] [PubMed] [Google Scholar]

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