Skip to main content

Advertisement

SpringerLink
Log in

ACTH Enhancement of T-Lymphocyte Cytotoxic Responses

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. Corticotropin (ACTH) was one of the first neuropeptides shown to bind to receptors on leukocytes and modulate immune responses. Generally ACTH inhibits immune responses, but certain functions can be enhanced. The present study was performed to determine the effects of ACTH on cytotoxic T-lymphocyte responses, the components, and the major phenotypes of the participating cells.

2. The action of ACTH on cytotoxicity was measured in vitro, in assays utilizing T-lymphocytes that had been previously sensitized in vivo. The cells were then cultured with ACTH and target cells bearing the appropriate stimulatory major histocompatiblity antigens.

3. ACTH did not significantly affect a primary mixed lymphocyte reaction whereas it enhanced a secondary (memory) cytotoxic response up to 100% following 2 days of ACTH treatment. The effect was a shift in the kinetics of effector cell generation so that ACTH-treated cultures demonstrated an augmented cytotoxic activity on day 2, that was not as pronounced on day 3 as cytotoxic activity in control cultures became maximal. ACTH also inhibited Concanavalin A-stimulated T-lymphocyte mitogenesis. Immature thymocyte mitogenesis was inhibited more than that of mature thymocytes.

4. The finding that IFN-γ was elevated in the cultures suggested that ACTH may enhance memory cytotoxic responses through a combination of mechanisms such as direct cell alterations or synergy with regulatory cytokines. While corticosteroids are probably the most recognized neuroendocrine, stress hormone to affect immune functions, our study illustrates that other neuroendocrine factors such as ACTH, also directly affect immune functions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Akbulut, S., Byersdorfer, C. A., Larsen, C., Zimmer, S. L., Humphreys, T. D., and Clarke, B. L. (2001). Expression of the melanocortin 5 receptor on rat lymphocytes. Biochem. Biophys. Res. Commun. 281:1086–1092.

    Article  PubMed  Google Scholar 

  • Alvarez-Mon, M., Kehrl, J. H., and Fauci, A. S. (1985). A potential role for adrenocorticotropin in regulating human B lymphocyte functions. J. Immunol. 135:3823–3826.

    PubMed  Google Scholar 

  • Ashton-Rickardt, P. G., and Opferman, J. T. (1999). Memory T lymphocytes. Cell Mol. Life Sci. 56:69–77.

    Article  PubMed  Google Scholar 

  • Bhardwaj, R., Becher, E., Mahnke, K., Hartmeyer, M., Schwarz, T., Scholzen, T., and Luger, T. A. (1997). Evidence for the differential expression of the functional alpha-melanocyte-stimulating hormone receptor MC-1 on human monocytes. J. Immunol. 158:3378–3384.

    PubMed  Google Scholar 

  • Bost, K. L., Clarke, B. L., Xu, J. C., Kiyono, H., McGhee, J. R., and Pascual, D. (1990). Modulation of IgM secretion and H chain mRNA expression in CH12.LX.C4.5F5 B cells by adrenocorticotropic hormone. J. Immunol. 145:4326–4331.

    PubMed  Google Scholar 

  • Campbell, J. B., Grunberger, J., Kochman, M. A., and White, S. L. (1975). A microplaque reduction assay for human and mouse interferon. Can. J. Microbiol 21:1247–1253.

    PubMed  Google Scholar 

  • Catania, A., Rajora, N., Capsoni, F., Minonzio, F., Star, R. A., and Lipton, J. M. (1996). The neuropeptide alpha-MSH has specific receptors on neutrophils and reduces chemotaxis in vitro. Peptides 17:675–679.

    Article  PubMed  Google Scholar 

  • Clarke, B. L., and Bost, K. L. (1989). Differential expression of functional adrenocorticotropic hormone receptors by subpopulations of lymphocytes. J. Immunol. 143:464–469.

    PubMed  Google Scholar 

  • Cohen, S., Tyrrell, D., and Smith, A. P. (1991). Psychological stress and susceptibility to the common cold. N. Engl. J. Med. 1991:606–612.

    Google Scholar 

  • DuPont, A. G., Somers, G., Van Steirteghem, A. C., Warson, F., and Vanhaelst, L. (1984). Ectopic adrenocorticotropin production: Disappearance after removal of inflammatory tissue. J. Clin. Endocrinol Metab 58:654–658.

    PubMed  Google Scholar 

  • Galvan, M., Murali-Krishna, K., Ming, L. L., Baum, L., and Ahmed, R. (1998). Alterations in cell surface carbohydrates on T cells from virally infected mice can distinguish effector/memory CD8+ T cells from naive cells. J. Immunol. 161:641–648.

    PubMed  Google Scholar 

  • Glaser, R., Kiecolt-Glaser, J. K., Bonneau, R. H., Malarkey, W. B., Kennedy, S., and Hughes, J. (1992). Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychom. Med. 54:22–29.

    Google Scholar 

  • Hartmeyer, M., Scholzen, T., Becher, E., Bhardwaj, R. S., Schwarz, T., and Luger, T.A. (1997). Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocyte-stimulating hormone. J. Immunol. 159:1930–1937.

    PubMed  Google Scholar 

  • Heijnen, C. J., Zijlstra, J., Kavelaars, A., Croiset, G., and Ballieux, R. E. (1987). Modulation of the immune response by POMC-derived peptides. I. Influence on proliferation of human lymphocytes. Brain Behav. Immun. 1:284–291.

    Article  PubMed  Google Scholar 

  • Hughes, T. K., and Smith, E. M. (1989). Corticotropin (ACTH) induction of tumor necrosis factor alpha by monocytes. J. Biol. Regul. Homeost. Agents 3:163–166.

    PubMed  Google Scholar 

  • Johnson, E. W. (1989) Distribution, modulation, and function of murine leukocyte adrenocorticotropin receptors: a dissertation, pp. 1–117. University of Texas Medical Branch, Galveston.

    Google Scholar 

  • Johnson, E. W., Blalock, J. E., and Smith, E. M. (1988). ACTH receptor-mediated induction of leukocyte cyclic AMP. Biochem. Biophys. Res. Commun. 157:1205–1211.

    Article  PubMed  Google Scholar 

  • Johnson, E. W., Hughes, T. K., and Smith, E. M. (2001). ACTH receptor distribution and modulation among murine mononuclear leukocyte populations. J. Biol. Regul. Homeost. Agents 15:156–162.

    PubMed  Google Scholar 

  • Johnson, H. M., Smith, E. M., Torres, B. A., and Blalock, J. E. (1982). Regulation of the in vitro antibody response by neuroendocrine hormones. Proc. Natl Acad. Sci USA 79:4171–4174.

    PubMed  Google Scholar 

  • Johnson, H. M., Torres, B. A., Smith, E. M., Dion, L. D., and Blalock, J. E. (1984). Regulation of lymphokine (gamma-interferon) production by corticotropin. J. Immunol. 132:246–250.

    PubMed  Google Scholar 

  • Kavelaars, A., Ballieux, R. E., and Heijnen, C. (1988). Modulation of the immune response by proopiomelanocortin derived peptides. II. Influence of adrenocorticotropic hormone on the rise in intracellular free calcium concentration after T cell activation. Brain Behav. Immun. 2:57–66.

    Article  PubMed  Google Scholar 

  • Kiecolt-Glaser, J. K., Glaser, R., Gravenstein, S., Malarkey, W. B., and Sheridan, J. (1996). Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc. Natl. Acad. Sci. USA 93:3043–3047.

    Article  PubMed  Google Scholar 

  • Koff, W. C., and Dunegan, M. A. (1985). Modulation of macrophage-mediated tumoricidal activity by neuropeptides and neurohormones. J. Immunol. 135:350–354.

    PubMed  Google Scholar 

  • MacDonald, H. R., Cerottini, J. C., Ryser, J. E., Maryanski, J. L., Taswell, C., Widmer, M. B., and Brunner, K. T. (1980). Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol. Rev. 51:93–123.

    PubMed  Google Scholar 

  • McEwen, B. S., Biron, C. A., Brunson, K. W., Bulloch, K., Chambers, W. H., Dhabhar, F. S., Goldfarb, R. H., Kitson, R. P., Miller, A. H., Spencer, R. L., and Weiss, J. M. (1997). The role of adrenocorticoids as modulators of immune function in health and disease: Neural, endocrine and immune interactions. Brain Res. Rev. 23:79–133.

    Article  PubMed  Google Scholar 

  • Meyer, III, W. J., Smith, E. M., Richards, G. E., Cavallo, A., Morrill, A. C., and Blalock, J. E. (1987). In vivo immunoreactive adrenocorticotropin (ACTH) production by human mononuclear leukocytes from normal and ACTH-deficient individuals. J. Clin. Endocrinol. Metabol 64:98–105.

    Google Scholar 

  • Mishell, B. B., and Shiigi, S. M. (1980) Selected Methods in Cellular Immunol. pp. 1–486. W. H. Freeman, San Francisco.

    Google Scholar 

  • Reisner, Y., Linker-Israeli, M., and Sharon, N. (1976). Separation of mouse thymocytes into two subpopulations by the use of peanut agglutinin. Cell Immunol. 25:129–134.

    Article  PubMed  Google Scholar 

  • Schioth, H. B., Chhajlani, V., Muceniece, R., Klusa, V., and Wikberg, J. E. (1996). Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. Life Sci. 59:797–801.

    Article  PubMed  Google Scholar 

  • Sheridan, J. F. (1998). Norman Cousins Memorial Lecture 1997. Stress-induced modulation of anti-viral immunity. Brain Behav. Immun. 12:1–6.

    Article  PubMed  Google Scholar 

  • Smith, E. M. (1994). Corticotropin and Immunoregulation.in by Scharrer, B E., Smith, M., and Stefano, G. B. (eds), Neuropeptides and Immunoregulation. Springer-Verlag, Berlin, pp. 28–45.

    Google Scholar 

  • Smith, E. M., and Blalock, J. E. (1981). Human lymphocyte production of corticotropin and endorphin-like substances: Association with leukocyte interferon. Proc. Natl Acad. Sci. USA 78:7530–7534.

    PubMed  Google Scholar 

  • Smith, E. M., Brosnan, P., Meyer, W. J., and Blalock, J. E. (1987). An ACTH receptor on human mononuclear leukocytes. Relation to adrenal ACTH-receptor activity. N. Engl. J. Med. 317:1266–1269.

    PubMed  Google Scholar 

  • Smith, E. M., Galin, F. S., LeBoeuf, R. D., Coppenhaver, D. H., Harbour, D. V., and Blalock, J. E. (1990). Nucleotide and amino acid sequence of lymphocyte-derived corticotropin: Endotoxin induction of a truncated peptide. Proc. Natl. Acad. Sci. USA 87:1057–1060.

    PubMed  Google Scholar 

  • Smith, E. M., Hughes, T. K., Jr., Hashemi, F., and Stefano, G. B. (1992). Immunosuppressive effects of corticotropin and melanotropin and their possible significance in human immunodeficiency virus infection. Proc Natl Aca Sci USA 89:782–786.

    Google Scholar 

  • Smith, E. M., Johnson, H. M., and Blalock, J. E. (1983). Staphylococcus aureus protein A induces the production of interferon-alpha in human lymphocytes and interferon-alpha/beta in mouse spleen cells. J. Immunol. 130:773–776.

    PubMed  Google Scholar 

  • Smith, E. M., Meyer, W. J., and Blalock, J. E. (1982). Virus-induced corticosterone in hypophysectomized mice: A possible lymphoid adrenal axis. Science 218:1311–1312.

    PubMed  Google Scholar 

  • Sprent, J. (2003). Turnover of memory-phenotype CD8+ T cells. Microbes Infect. 5:227–231.

    Article  PubMed  Google Scholar 

  • Sprent, J., and Surh, C. D. (2001). Generation and maintenance of memory T cells. Curr. Opin. Immun. 13:248–254.

    Article  Google Scholar 

  • Sprent, J., and Surh, C. D. (2002). T cell memory. Annu. Rev. Immun. 20:551–579.

    Article  PubMed  Google Scholar 

  • Star, R. A., Rajora, N., Huang, J., Stock, R. C., Catania, A., and Lipton, J. M. (1995). Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. Proc. Natl Acad. Sci. USA 92:8016–8020.

    PubMed  Google Scholar 

  • Stefano, G. B., and Smith, E. M. (1996). Adrenocorticotropin–a central trigger in immune responsiveness: Tonal inhibition of immune activation. Med. Hypo. 46:471–478.

    Article  Google Scholar 

  • Stein, C., Hassan, A. H., Przewlocki, R., Gramsch, C., Peter, K., and Herz, A. (1990). Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc. Natl. Acad. Sci USA 87:5935–5939.

    PubMed  Google Scholar 

  • Swain, S. L. (2003). Regulation of the generation and maintenance of T-cell memory: A direct, default pathway from effectors to memory cells. Microbes Infect. 5:213–219.

    Article  PubMed  Google Scholar 

  • Tomiyama, H., Matsuda, T., and Takiguchi, M. (2002). Differentiation of human CD8+ T cells from a memory to memory/effector phenotype. J. Immunol. 168:5538–5550.

    PubMed  Google Scholar 

  • Wikberg, J. E. (1999). Melanocortin receptors: perspectives for novel drugs. Eur. J. Pharmacol. 375:295–310.

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Eve W. Johnson

    Present address: Eve Johnson Wilson, Medicalliance, Inc. 5565 Sterrett Place, Ste. 200, Columbia, Maryland, 21044

Authors and Affiliations

  1. Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, 77555

    Eve W. Johnson, Thomas K. Hughes Jr & Eric M. Smith

  2. Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, Texas, 77555

    Eric M. Smith

Authors
  1. Eve W. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas K. Hughes Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric M. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric M. Smith.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnson, E.W., Hughes, T.K. & Smith, E.M. ACTH Enhancement of T-Lymphocyte Cytotoxic Responses. Cell Mol Neurobiol 25, 743–757 (2005). https://doi.org/10.1007/s10571-005-3972-8

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-005-3972-8

Key Words

Search

Navigation