Immunoregulatory effects of α-endorphin, β-endorphin, methionine-enkephalin, and adrenocorticotropic hormone on anti-tetanus toxoid antibody synthesis by human lymphocytes

doi:10.1016/0090-1229(89)90152-9

Clinical Immunology and Immunopathology

Volume 52, Issue 3, September 1989, Pages 376-385

Clinical Immunology ...

https://doi.org/10.1016/0090-1229(89)90152-9 Get rights and content

Abstract

This study assesses the effects of adrenocorticotropic hormone (ACTH), α-endorphin (α-endo), β-endorphin (β-endo), and methionine-enkephalin (met-enk) on tetanus toxoidstimulated in vitro specific antibody (anti-TT) synthesis. ACTH and TT-costimulated cultures enhanced antibody (Ab) synthesis over control TT-stimulated cultures at 10⁻⁹ and 10⁻¹¹M and suppressed Ab synthesis at 10⁻¹³ and 10⁻¹⁷M. The α-endo and TT-costimulated cultures enhanced Ab synthesis over control cultures at all concentrations tested (10⁻⁷ to 10⁻¹⁵M). Cultures costimulated with β-endo and TT enhanced Ab synthesis over control cultures at 10⁻¹¹M and suppressed Ab synthesis at doses above and below 10⁻¹¹M. The met-enk and TT-costimulated cultures produced more Ab than controls at 10⁻⁹M; and the met-enk and TT-costimulated cultures produced less Ab than controls at other concentrations as low as 10⁻¹⁷M and as high as 10⁻⁷M. The results of this study provide one reason as to why the interactions between the neuroendocrine and immune systems remain unclear.

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Cited by (37)

T lymphocyte proliferation is suppressed by the opioid growth factor ([Met<sup>5</sup>]-enkephalin)-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases
2011, Immunobiology
Citation Excerpt :
In the case of β endorphin, studies report an increase (Hemmick and Bidlack 1990; Gilmore and Weiner 1989; Kusnecov et al. 1987) and decrease (Marchini et al. 1995; Hough et al. 1990; Shahabi et al. 1991) in T lymphocyte response. With regard to [Met5]-enkephalin (OGF), investigators found an increase (Kowalski 1998a,b; Hucklebridge et al. 1990, 1989; Plotnikoff and Miller 1983), decrease (Kamphuis et al. 1998; Shahabi and Sharp 1995; Ohmori et al. 2009; Marić and Janković 1987), or no effect (Gilman et al. 1982; Wybran 1985; Owen et al. 1998; Munn and Lum 1989; Zunich and Kirkpatrick 1988; van den Bergh et al. 1993; Prete et al. 1986; Kusnecov et al. 1989), on T lymphocytes. The results of the present study reveal that only exogenously delivered OGF at concentrations ranging from 10−4 to 10−7 M had an effect on altering T lymphocyte proliferation, and only if the cultures were stimulated.
Opioid peptides function as immunomodulatory molecules. Reports have linked the opioid growth factor (OGF), [Met⁵]-enkephalin, and its receptor OGFr to autoimmune diseases. OGF repressed the incidence and magnitude of myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis in mice. Given the extensive connection between the immune system and autoimmune diseases, the present study was conducted to examine the relationship of the OGF–OGFr axis and T lymphocyte proliferation. Splenic-derived mouse lymphocytes were stimulated with phytohemagglutin (PHA). All non-stimulated and PHA-stimulated T lymphocytes had immunoreactivity for OGF-like enkephalin and OGFr. OGF markedly suppressed T lymphocyte number in a dose-dependent manner. However, PHA-stimulated T lymphocytes were not altered in cell number by a variety of natural and synthetic opioid-related compounds, some specific for μ, δ, and κ opioid receptors. Persistent blockade of opioid receptors with the general opioid antagonist naltrexone (NTX), as well as antibody neutralization of OGF-like peptides, had no effect on cell number. Non-stimulated T lymphocytes exhibited no change in cell number when subjected to OGF or NTX. Treatment of T lymphocytes with siRNAs for μ, δ, or κ opioid receptors did not affect cell number, and the addition of OGF to these siRNA-exposed cultures depressed the population of cells. T lymphocytes treated with OGFr siRNA also had a comparable number of cells to control cultures, but the addition of OGF did not alter cell number. DNA synthesis in PHA-stimulated T lymphocytes exposed to OGF was markedly decreased from PHA-stimulated cultures receiving vehicle, but the number of cells undergoing apoptosis or necrosis in these cultures was similar to control levels. T lymphocytes subjected to siRNA for p16 and/or p21 had a comparable number of cells compared to controls, and treatment with OGF did not depress cell number in preparations transfected with both p16 and p21 siRNA. These data reveal that the OGF–OGFr axis is present in T lymphocytes and is capable of suppressing cell proliferation. However, T lymphocytes are not dependent on the regulation of cell proliferation by this system. The results showing that the OGF–OGFr axis is an immunosuppressant, offers explanation for reports that autoimmune diseases can be modulated by this system.
Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis
2008, Brain, Behavior, and Immunity
There exists a bidirectional regulatory circuit between the nervous and immune systems. This regulation has been shown to be mediated in part through neuroendocrine hormones and cytokines. Both systems have receptors for both types of signal molecules. The nervous system has receptors for cytokines and it also synthesizes cytokines. The immune system synthesizes and responds to cytokines. So, it is not too farfetched to believe that neuroendocrine peptide hormones could bind to leukocytes and modulate immune functions. However, it is not widely known that the immune system also synthesizes functional, neuropeptide hormones. This will be discussed in this paper citing a plethora of evidence. The aim of this paper is to summarize this evidence by using three neuropeptides that are synthesized by leukocytes and modulate immune functions as examples; corticotropin (ACTH), endorphin (END), and corticotropin releasing factor (CRF). The production and action of these three neuropeptides in the immune system will be explained. Finally, the potential physiological role of leukocyte-derived ACTH, END, and CRF in inflammation as a localized hypothalamic–pituitary-like axis is discussed.
Role of endogenous pro-enkephalin A-derived peptides in human T cell proliferation and monocyte IL-6 production
1998, Journal of Neuroimmunology
In this paper, we describe that met-enkephalin and/or enkephalin-containing intermediary peptides of the prohormone pro-enkephalin A are produced and secreted by human peripheral blood T cells and monocytes. The peptides are produced after stimulation with the mitogenic monoclonal antibodies anti-CD2.1/2.2 and anti-CD28. In monocytes, enkephalin synthesis was induced by stimulation with lipopolysaccharide. We demonstrate here that these immune cell-derived enkephalins play an important regulatory role in the immune response. By using an anti-sense oligonucleotide strategy we could block the production of enkephalins. Blockade of the production of met-enkephalin and enkephalin-containing intermediary peptides resulted in enhancement of the proliferative T cell response and inhibition of monocyte IL-6 secretion. In vitro reconstitution of the anti-sense treated cultures with synthetic met-enkephalin or the delta-type specific opioid receptor agonist deltorphin could reverse inhibition of monocyte IL-6 production, suggesting that endogenous enkephalins act via membrane opioid receptors. In contrast, addition of met-enkephalin or deltorphin to the anti-sense treated T cell cultures did not have any effect on T cell proliferation.
T helper 2 cytokines induce preproenkephalin mRNA expression and proenkephalin A in human peripheral blood mononuclear cells
1997, Journal of Neuroimmunology
We investigated the regulatory influence of several cytokines on the expression of preproenkephalin (PPE) mRNA in human peripheral blood mononuclear cells (PBMC). By use of a quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR), we demonstrate that the T helper 2 cytokines IL-4 and IL-10 are more potent in upregulating PPE mRNA expression in human PBMC than the T helper 1 cytokines IL-2 and γ-IFN. In addition, TGF-β is also an effective inducer of PPE mRNA. TGF-β, IL-4 and IL-10 increase the cytoplasmatic concentration of met-enkephalin in PBMC. Secretion of met-enkephalin in the culture supernatant of IL-4- or IL-10-stimulated PBMC could not be observed, but proenkephalin A-derived met-enkephalin containing peptides could be demonstrated. IL-4 and IL-10 do not induce PPE mRNA via the same pathways. We could observe that PKA is involved in IL-4 mediated PPE mRNA induction, whereas IL-10 apparently uses another route.
Pro-opiomelanocortin gene expression and protein processing in rat mononuclear leukocytes
1997, Journal of Neuroimmunology
Although production of pro-opiomelanocortin (POMC) mRNA and POMC-derived peptides in extrapituitary tissues, including immune tissues, has been demonstrated, questions remain concerning the nature of POMC transcripts and peptide products. With regard to POMC gene expression in lymphocytes, the expression of full-length mRNA and POMC has been questioned. In the present report, we have tested for the existence of these molecules. Western blot analysis with an antibody against POMC-derived adrenocorticotropic hormone (ACTH) specifically identified identical immunoreactive (ir) species in both rat anterior pituitary (AP) and splenocyte cell extracts. The relative molecular weights were those expected for nonglycosylated ACTH, as well as its biosynthetic intermediate, and POMC. Mitogen stimulation of splenic mononuclear cells (MNC) enhanced the levels of these three molecular species. Primer extension analysis identified a band which migrated with a size equivalent to a full-length POMC transcript (~816 nt) in both mitogen-stimulated MNC and AP mRNA. Macrophages produced POMC protein and mRNA among unstimulated splenocytes, while lymphocytes could be induced to produce POMC mRNA upon stimulation. 5′ RACE-tailed PCR products were cloned and sequenced. A mRNA encoding all three POMC exons was identified in Concanavalin A (ConA)-stimulated MNC and was identical to that from the anterior pituitary. These results unequivocally demonstrate that mononuclear cells produce full-length POMC transcripts. Its regulation in lymphocytes is distinct from that in macrophages which constitutively produce POMC-derived peptides and mRNA. Also, the biosynthetic pathway of ACTH from POMC in splenic MNC stimulated with ConA appears to be identical to that in rat corticotrophs.
Ultralow concentrations of proenkephalin and [met<sup>5</sup>]-enkephalin differentially affect IgM and IgG production by B cells
1997, Journal of Neuroimmunology
Resting mouse splenic B cells were activated with lipopolysaccharide/dextran sulfate (LPS/DxS) to measure both B cell proliferation and IgM/IgG isotype production when increasing concentrations of [Met⁵]-enkephalin (MENK) and proenkephalin (PENK) (10⁻¹⁶ to 10⁻⁸ M) were added at increasing times after B cell activation (0, 3, 6, or 24 h). Results show that proliferation was not affected by either peptide, but that IgM, IgG3 and IgG2a production were inhibited in a concentration- and time-dependent manner by MENK. IgG1 production was unaffected by MENK. In contrast, PENK induced no change in the production of Ig isotypes at any time point of addition, with the exception of IgG1 and IgG2a that were enhanced when PENK was added 6 h after cell activation. In the absence of LPS/DxS activation, no change in the level of any Ig isotype was induced by either peptide.

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¹: Present address: Division of Hematology-Oncology, Wayne State University, P.O. Box 02188, Detroit, MI 48201-199.

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Regular articleImmunoregulatory effects of α-endorphin, β-endorphin, methionine-enkephalin, and adrenocorticotropic hormone on anti-tetanus toxoid antibody synthesis by human lymphocytes

Abstract

Biochem. Pharmacol.

Life Sci.

Clin. Immunol. Immunopathol.

Prog. Brain Res.

Clin. Immunol. Immunopathol.

Clin. Immunol. Immunopathol.

Drug Alcohol Depend.

Neuropharmacology

Science

Nature (London)

Nature (London)

Sci. Amer.

J. Immunol.

Regular article
Immunoregulatory effects of α-endorphin, β-endorphin, methionine-enkephalin, and adrenocorticotropic hormone on anti-tetanus toxoid antibody synthesis by human lymphocytes