Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients

Li,Cai-Xia; Liang,Dong-Dong; Xie,Guo-Hao; Cheng,Bao-Li; Chen,Qi-Xing; Wu,Shui-Jing; Wang,Jun-Lu; Cho,William; Fang,Xiang-Ming

doi:10.3892/mmr.2013.1331

Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients

Authors:
- Cai-Xia Li
- Dong-Dong Liang
- Guo-Hao Xie
- Bao-Li Cheng
- Qi-Xing Chen
- Shui-Jing Wu
- Jun-Lu Wang
- William Cho
- Xiang-Ming Fang
View Affiliations

Affiliations: Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China, Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, P.R. China, Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, P.R. China
Published online on: February 20, 2013 https://doi.org/10.3892/mmr.2013.1331
Pages: 1117-1122

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Inflammatory and immune responses, as well as melatonin secretion, are affected by circadian regulation. Abnormal circadian rhythm of melatonin release has been reported to be associated with the later stages of sepsis; however, its role in the early stages of sepsis is unclear. We studied 11 septic and 11 non-septic patients in our intensive care unit (ICU). Peripheral blood was drawn at 4-h intervals on the first day, beginning at 2:00 p.m., over a total period of 24 h. Plasma levels of melatonin, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA). Messenger RNA levels of circadian genes Cry-1 and Per-2 were analyzed using quantitative real-time PCR. Results show the circadian rhythm of melatonin secretion was altered in the early stages of sepsis. The melatonin secretion acrophase occurred earlier in septic patients at 6:00 p.m., compared with at 2:00 a.m. in non-septic ICU patients. Compared with the non-septic group, both Cry-1 and Per-2 expression were significantly decreased while TNF-α and IL-6 expression were significantly increased in septic patients [TNF-α, 64.1 (43.6-89.1) vs. 11.4 (10.4‑12.5) ng/ml; IL-6, 41.2 (35.7-50.8) vs. 19.1 (16-136.7) ng/ml; median (range), both P=0.04]. The peak concentrations of TNF-α and IL-6 were shown to be in concordance with the rhythm of melatonin secretion. The circadian rhythm of melatonin secretion and circadian gene expression were altered in the early stages of sepsis, which likely led to the changes in pro-inflammatory cytokine release. These findings shed light on the potential link between circadian rhythm and the progression of early‑stage sepsis.

View Figures

View References

1	Mackenzie I and Lever A: Management of sepsis. Br Med J. 335:929–932. 2007. View Article : Google Scholar
2	Dellinger RP, Levy MM, Carlet JM, Bion J and Parker MM: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med. 36:296–327. 2008. View Article : Google Scholar
3	Riedemann NC, Guo RF and Ward PA: The enigma of sepsis. J Clin Invest. 112:460–467. 2003. View Article : Google Scholar : PubMed/NCBI
4	Chima RS, Hake PW, Piraino G, Mangeshkar P and Denenberg A: Ciglitazone ameliorates lung inflammation by modulating the inhibitor κB protein kinase/nuclear factor-κB pathway after hemorrhagic shock. Crit Care Med. 36:2849–2857. 2008.PubMed/NCBI
5	Lubbers T, De Haan JJ, Hadfoune M, Zhang Y and Luyer MD: Lipid-enriched enteral nutrition controls the inflammatory response in murine Gram-negative sepsis. Crit Care Med. 38:1996–2002. 2010.PubMed/NCBI
6	Dorresteijn MJ, Visser T, Cox LA, Bouw MP and Pillay J: C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia. Crit Care Med. 38:2139–2145. 2010. View Article : Google Scholar : PubMed/NCBI
7	Pevet P and Challet E: Melatonin: both master clock output and internal time-giver in the circadian clocks network. J Physiol Paris. 105:170–182. 2011. View Article : Google Scholar : PubMed/NCBI
8	Brzezinski A: Melatonin in humans. N Engl J Med. 336:186–195. 1997. View Article : Google Scholar
9	Escames G, Leon J, Macias M, Khaldy H and Acuna-Castroviejo D: Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J. 17:932–934. 2003.
10	Lee YD, Kim JY, Lee KH, Kwak YJ and Lee SK: Melatonin attenuates lipopolysaccharide-induced acute lung inflammation in sleep-deprived mice. J Pineal Res. 46:53–57. 2009. View Article : Google Scholar : PubMed/NCBI
11	Mundigler G, Delle-Karth G, koreny M, et al: Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med. 30:536–540. 2002. View Article : Google Scholar : PubMed/NCBI
12	Bourne RS and Mills GH: Melatonin: possible implications for the postoperative and critically ill patient. Intensive Care Med. 32:371–379. 2006. View Article : Google Scholar : PubMed/NCBI
13	Reppert SM and Weaver DR: Coordination of circadian timing in mammals. Nature. 418:935–941. 2002. View Article : Google Scholar : PubMed/NCBI
14	James FO, Cermakian N and Boivin DB: Circadian rhythms of melatonin, cortisol, and clock gene expression during simulated night shift work. Sleep. 30:1427–1436. 2007.PubMed/NCBI
15	O’Connor MF, Motivala SJ, Valladares EM, Olmstead R and Irwin MR: Sex differences in monocyte expression of IL-6: role of autonomic mechanisms. Am J Physiol Regul Integr Comp Physiol. 293:R145–R151. 2007.PubMed/NCBI
16	Haimovich B, Calvano J, Haimovich AD, Calvano SE and Coyle SM: In vivo endotoxin synchronizes and suppresses clock gene expression in human peripheral blood leukocytes. Crit Care Med. 38:751–758. 2010. View Article : Google Scholar : PubMed/NCBI
17	Pollard LC, Choy EH, Gonzalez J, Khoshaba B and Scott DL: Fatigue in rheumatoid arthritis reflects pain, not disease activity. Rheumatology (Oxford). 45:885–889. 2006. View Article : Google Scholar : PubMed/NCBI
18	American College of Chest Physicians/Society of Critical Care Medicine consensus conference. Definitions of sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 20:864–874. 1992. View Article : Google Scholar
19	Kusanagi H, Hida A and Satoh K: Expression profiles of 10 circadianclock genes in human peripheral blood mononuclear cells. Neurosci Res. 61:136–142. 2008. View Article : Google Scholar : PubMed/NCBI
20	Verceles AC, Silhan L and Terrin M: Circadian rhythm disruption in severe sepsis: the effect of ambient light on urinary 6-sulfatoxymelatonin secretion. Intensive Care Med. 38:804–810. 2012. View Article : Google Scholar : PubMed/NCBI
21	Liu J, Malkani G and Shi X: The circadian clock Period 2 gene regulates gamma interferon production of NK cells in host response to lipopolysaccharide-induced endotoxic shock. Infect Immun. 74:4750–4756. 2006. View Article : Google Scholar : PubMed/NCBI
22	Okada K, Yano M, Doki Y, Azama T and Iwanaga H: Injection of LPS causes transient suppression of biological clock genes in rats. J Surg Res. 145:5–12. 2008. View Article : Google Scholar : PubMed/NCBI
23	Teboul M, Barrat-Petit MA and Li XM: Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells. J Mol Med. 83:693–699. 2005. View Article : Google Scholar : PubMed/NCBI
24	Godin PJ and Buchman TG: Uncoupling of biological oscillators: A complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med. 24:1107–1111. 1996. View Article : Google Scholar
25	Steinhilber D, Brungs M, Werz O, Wiesenberg I and Danielsson C: The nuclear receptor for melatonin repress 5-lipoxygenase gene expression in human B lymphocytes. J Biol Chem. 270:7037–7040. 1995. View Article : Google Scholar : PubMed/NCBI
26	Deng WG, Tang ST, Tseng HP and Wu KK: Melatonin suppresses cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood. 108:518–524. 2006. View Article : Google Scholar : PubMed/NCBI
27	Carrillo-Vico A, Lardone PJ, Naji L, Fernandez-Santos JM and Martin-Lacave I: Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. J Pineal Res. 39:400–408. 2005. View Article : Google Scholar
28	Shang Y, Xu SP, Wu Y, Jinag YX and Wu ZY: Melatonin reduces acute lung injury in endotoxemic rats. Chin Med J(Engl). 122:1388–1393. 2009.PubMed/NCBI