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Dale HH, Dudley HW. The presence of histamine and acetylcholine in the spleen of the ox and the horse. J Physiol. 1929;68:97-123
Sir Henry Hallet Dale was born in 1875 in Islington, London, U.K. He visited Tollington Park College, The Leys School Cambridge, and in 1894 he entered Trinity College, Cambridge. In 1909, he received his Doctor of Medicine degree from Cambridge. Dale devoted his work to acetylcholine in studying its effects on various bodily functions (e.g., blood pressure). In parallel to this early work in the 1910s and 1920s, Otto Loewi (1873-1961) born in Frankfurt and working in Graz discovered that acetylcholine is a neurotransmitter from the vagus nerve (he called it the Vagusstoff). Dale and Loewi received the Nobel Prize in Physiology or Medicine in 1936 for their work on neurotransmission.
His partner in the publication of 1929 (1) was Harold Ward Dudley (1887-1935), born in Leeds, U.K. He studied chemistry at the University of Leeds, and he received his doctoral degree in chemistry in the environment of Emil Fischer at the University of Berlin in 1912. After a short stay in New York City and active participation in World War I, he joined the team of Henry Dale in the National Institute for Medical Research in Hampstead (London).
The discovery of Dale and Dudley
In their early paper of 1929, Dale and Dudley discovered, for the first time, acetylcholine in an animal body. For their discovery, they used the horse spleen, and they showed the physiological function of extracted acetylcholine (1). In this paper, they wrote in the discussion:
“It appears to us that the case for acetylcholine as a physiological agent is now materially strengthened by the fact that we have been able to isolate it from an animal organ and thus to show that it is a natural constituent of the body. We have yet no conception of the meaning of its presence in the spleens of these large ungulates [AU: hoofed animal].”
The discussion of the paper in 1929 clearly shows that Dale and Dudley had no idea why acetylcholine should be present in the spleen. They did not realize that it must be produced by immune or endothelial cells because their focus was not on the spleen as a reservoir of immune cells. Nevertheless, this first work clearly showed the non-neuronal acetylcholine release.
The discovery of acetylcholine in immune cells – Kawashima and colleagues
Today, we know that the spleen is not innervated by parasympathetic nerve fibers that carry acetylcholine as a neurotransmitter (3). Thus, production of acetylcholine in the spleen must depend on another cellular source. Indeed, acetylcholine can be produced from single cells very different from neuronal cells such as in fungi (4) or bacteria (5) (see also ref. 6 for more examples). The discovery of acetylcholine production in immune and endothelial cells lasted until the late 1980s and early 1990s (7-9). Today, we clearly recognize an extra-neuronal cholinergic system in immune cells (6). We also recognize immunomodulating effects through the nicotinic acetylcholine receptor alpha7 subunit (6, 10). Another neurotransmitter to be discovered in leukocytes was noradrenaline at the beginning of the 1990s (11,12). Release of acetylcholine in the spleen is independent of electrical tissue stimulation, which demonstrates its non-neuronal source (different for noradrenaline, ref. 13).
In one form or the other, the existence of the extra-neuronal cholinergic system in immune cells stood the test of time (6), and some relevant experiments have also been published in Neuroimmunomodulation (14-16).
References
- Dale HH, Dudley HW. The presence of histamine and acetylcholine in the spleen of the ox and the horse. J Physiol. 1929;68:97-123
- Dale HH. Harold Ward Dudley. 1887-1935. Obituary Notices of Fellows of the Royal Society 1935;1:595-606
- Fujii T, Mashimo M, Moriwaki Y, Misawa H, Ono S, Horiguchi K, Kawashima K. Expression and function of the cholinergic system in immune cells. Front Immunol. 2017;8:1085. doi: 10.3389/fimmu.2017.01085
- Ewins AJ. Acetylcholine, a new active principle of ergot. Biochem J. 1914;8:44-49
- Stephenson M, Rowatt E. The production of acetylcholine by a strain of lactobacillus plantarum – with an addendum on the isolation of acetylcholine as a salt of hexanitrodiphenylamine by Alyne K. Harrison. J Gen Microbiol 1947;1:279-98
- Kawashima K, Mashimo M, Nomura A, Fujii T. Contributions of Non-Neuronal Cholinergic Systems to the Regulation of Immune Cell Function, Highlighting the Role of α7 Nicotinic Acetylcholine Receptors. Int J Mol Sci. 2024;25:4564. doi: 10.3390/ijms25084564
- Kawashima K, Oohata H, Fujimoto K, Suzuki T. Extraneuronal localization of acetylcholine and its release upon nicotinic stimulation in rabbits. Neurosci Lett. 1989;104:336-339
- Kawashima K, Watanabe N, Oohata H, Fujimoto K, Suzuki T, Ishizaki Y, Morita I, Murota S. Synthesis and release of acetylcholine by cultured bovine arterial endothelial cells. Neurosci Lett. 1990;119:156-158
- Kawashima K, Kajiyama K, Suzuki T, Fujimoto K. Presence of acetylcholine in blood and its localization in circulating mononuclear leukocytes of humans. Biog Amines 1993;9:251–258.
- Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384-388
- Bergquist J, Tarkowski A, Ekman R, Ewing A. Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamine regulation of lymphocyte function via an autocrine loop. Proc Natl Acad Sci U S A. 1994;91:12912-12916
- Josefsson E, Bergquist J, Ekman R, Tarkowski A. Catecholamines are synthesized by mouse lymphocytes and regulate function of these cells by induction of apoptosis. Immunology 1996;88:140-146
- Straub RH, Rauch L, Fassold A, Lowin T, Pongratz G. Neuronally released sympathetic neurotransmitters stimulate splenic interferon-gamma secretion from T cells in early type II collagen-induced arthritis. Arthritis Rheum. 2008;58:3450-3460
- Rinner I, Globerson A, Kawashima K, Korsatko W, Schauenstein K. A possible role for acetylcholine in the dialogue between thymocytes and thymic stroma. Neuroimmunomodulation. 1999;6:51-55.
- van der Zanden EP, Hilbers FW, Verseijden C, van den Wijngaard RM, Skynner M, Lee K, Ulloa L, Boeckxstaens GE, de Jonge WJ. Nicotinic acetylcholine receptor expression and susceptibility to cholinergic immunomodulation in human monocytes of smoking individuals. Neuroimmunomodulation. 2012;19:255-265
- Aripaka SS, Mikkelsen JD. Anti-Inflammatory Effect of Alpha7 Nicotinic Acetylcholine Receptor Modulators on BV2 Cells. Neuroimmunomodulation. 2020;27:194-202
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