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.
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.
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.
Ashton-Rickardt, P. G., and Opferman, J. T. (1999). Memory T lymphocytes. Cell Mol. Life Sci. 56:69–77.
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.
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.
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.
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.
Clarke, B. L., and Bost, K. L. (1989). Differential expression of functional adrenocorticotropic hormone receptors by subpopulations of lymphocytes. J. Immunol. 143:464–469.
Cohen, S., Tyrrell, D., and Smith, A. P. (1991). Psychological stress and susceptibility to the common cold. N. Engl. J. Med. 1991:606–612.
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.
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.
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.
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.
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.
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.
Johnson, E. W. (1989) Distribution, modulation, and function of murine leukocyte adrenocorticotropin receptors: a dissertation, pp. 1–117. University of Texas Medical Branch, Galveston.
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.
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.
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.
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.
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.
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.
Koff, W. C., and Dunegan, M. A. (1985). Modulation of macrophage-mediated tumoricidal activity by neuropeptides and neurohormones. J. Immunol. 135:350–354.
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.
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.
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.
Mishell, B. B., and Shiigi, S. M. (1980) Selected Methods in Cellular Immunol. pp. 1–486. W. H. Freeman, San Francisco.
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.
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.
Sheridan, J. F. (1998). Norman Cousins Memorial Lecture 1997. Stress-induced modulation of anti-viral immunity. Brain Behav. Immun. 12:1–6.
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.
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.
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.
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.
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.
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.
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.
Sprent, J. (2003). Turnover of memory-phenotype CD8+ T cells. Microbes Infect. 5:227–231.
Sprent, J., and Surh, C. D. (2001). Generation and maintenance of memory T cells. Curr. Opin. Immun. 13:248–254.
Sprent, J., and Surh, C. D. (2002). T cell memory. Annu. Rev. Immun. 20:551–579.
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.
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.
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.
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.
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.
Wikberg, J. E. (1999). Melanocortin receptors: perspectives for novel drugs. Eur. J. Pharmacol. 375:295–310.
Author information
Authors and Affiliations
Corresponding author
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10571-005-3972-8