Sleep and immune health: How dogs, goats and 'factor S' shaped a field

Abstract

Chronic insufficient sleep kills! Although this statement has high 'face validity', it is only recently that empirical evidence existed to support it. There are now sufficient data for numerous meta-analyses and systematic reviews to demonstrate that chronic insufficient sleep is associated with many inflammatory pathologies that are a public health burden. As a result, it is now well accepted that sleep is important for physical and mental health. This awareness derives from research that began in the late 19th and early 20th centuries and continues to the present day. In this narrative review we trace this rich history within the context of the research contributions of Professor James Krueger and his colleagues. The historic and current research by Professor Krueger and colleagues is fundamental to the many ongoing pre-clinical and clinical research programs focused on all aspects of sleep and immune health.

Keywords: Cytokine; Immunomodulator; Innate immune system; Interleukin; Public health; Sleep deprivation; Sleep factor.

Graphical abstract

Fig. 1

Left to right: John Pappenheimer, Manfred Karnovsky, Jim Krueger.

Fig. 2

Attendees at the US – Japan joint seminar on endogenous sleep factors. November 1988, Honolulu, HI.

Fig. 3

Members of the Krueger laboratory, Department of Physiology, University of Tennessee Memphis (1992). The laboratory was multi-national with members from the United States, Hungary, Italy, Germany, Japan, China and Russia. Not pictured: Luca Imeri, who had returned to Italy shortly before this picture was taken. Back row, left to right: Mark Opp; Levente Kapas; Jim Krueger; Edward Fincher, 4th; Jidong Fang; Sebastian Bredow Middle row, left to right: Lielie Hong; Linda Toth; Sandi Johnson; Linda Payne; Ferenc Obál, Jr. Front row, left to right (seated): Sema Geller; Gail Richmond; Mayumi Kimura-Takeuchi.

Fig. 4

Maria Grazia de Simoni, Mario Negri Institute for Pharmacological Research in Milan, Italy and Luca Imeri, Institute of Human Physiology II, University of Milan, Italy, 1992.

Fig. 5

Sleep regulatory system [as published in 2001]. Extensive evidence exists showing that the sub-stances illustrated are involved in sleep regulation (see text). These substances affect the pro-duction or action of one another. Collectively, these actions form the biochemical cascade illustrated. Arrows (→) indicate activation or enhanced production; (–) indicates an inhibitory effect. Substances in boxes inhibit NREMS, while other substances enhance NREMS. Many of those substances that promote sleep are growth factors (e.g., IL1, TNF, BDNF, NGF, IL-2, NO, PGs, adenosine, NFκB) and are upregulated by neuronal activity (e.g., IL1, TNF, BDNF, NGF, adenosine, NO). We have hypothesized that sleep mechanisms involve these neuron-activity-dependent substances and that sleep function is related to synaptic efficacy (see text). Abbreviations: LPs, lipopolysaccharides; MPs, muramyl peptides; dsRNA, double-stranded RNA; IL1RA, interleukin-1 receptor antagonist; sIL1R, soluble IL1 receptor; anti-IL1, anti-IL1 antibodies; CRH, corticotropin-releasing hormone; PGE 2, prostaglandin E 2 ; αMSH, αmelanocyte-stimulating hormone; IL1, interleukin-1; TNF, tumor necrosis factor; sTNFR, soluble TNF receptor; anti-TNF, anti-TNF antibodies; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; NFκB, nuclear factor kappa B; IL4, interleukin-4; IL10, inter-leukin-10; IL13, interleukin-13; TGFβ, transforming growth factor β; L-NAME, an arginine analog; NOS, nitric oxide synthase; COX-2, cyclooxygenase-2; IL2, interleukin-2; IGF-1,insulin-like growth factor 1; anti-GHRH, anti-GHRH antibodies; GHRH, growth hormone releasing hormone; NO, nitric oxide; PGD2, prostaglandin D 2; A1R, the adenosine A1 receptor; GABA, γ-aminobutyric acid; glu, glutamic acid. Reprinted with permission from (Krueger et al., 2001).