Inhibition of Interleukin-6 Trans-signaling in the Brain Facilitates Recovery from Lipopolysaccharide-induced Sickness Behavior

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2011 May 21

PMID 21595956

Citations 58

Authors

Michael D Burton

Nathan L Sparkman

Rodney W Johnson

Affiliations

Soon will be listed here.

Abstract

Background: Interleukin (IL)-6 is produced in the brain during peripheral infection and plays an important but poorly understood role in sickness behavior. Therefore, this study investigated the capacity of soluble gp130 (sgp130), a natural inhibitor of the IL-6 trans-signaling pathway to regulate IL-6 production in microglia and neurons in vitro and its effects on lipopolysaccharide (LPS)-induced sickness behavior in vivo.

Methods: A murine microglia (BV.2) and neuronal cell line (Neuro.2A) were used to study the effects of stimulating and inhibiting the IL-6 signaling pathway in vitro. In vivo, adult (3-6 mo) BALB/c mice received an intracerebroventricular (ICV) injection of sgp130 followed by an intraperitoneal (i.p.) injection of LPS, and sickness behavior and markers of neuroinflammation were measured.

Results: Soluble gp130 attenuated IL-6- and LPS-stimulated IL-6 receptor (IL-6R) activation along with IL-6 protein release in both microglial (BV.2) and neuronal (Neuro.2A) cell types in vitro. Moreover, in vivo experiments showed that sgp130 facilitated recovery from LPS-induced sickness, and this sgp130-associated recovery was paralleled by reduced IL-6 receptor signaling, mRNA, and protein levels of IL-6 in the hippocampus.

Conclusions: Taken together, the results show that sgp130 may exert an anti-inflammatory effect on microglia and neurons by inhibiting IL-6 binding. These data indicate that sgp130 inhibits the LPS-induced IL-6 trans-signal and show IL-6 and its receptor are involved in maintaining sickness behavior.

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References

Krzyszton C, Sparkman N, Grant R, Buchanan J, Broussard S, Woods J . Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation. Am J Physiol Regul Integr Comp Physiol. 2008; 295(4):R1109-14. PMC: 2576089. DOI: 10.1152/ajpregu.90302.2008. View

Richwine A, Godbout J, Berg B, Chen J, Escobar J, Millard D . Improved psychomotor performance in aged mice fed diet high in antioxidants is associated with reduced ex vivo brain interleukin-6 production. Brain Behav Immun. 2005; 19(6):512-20. DOI: 10.1016/j.bbi.2004.12.005. View

Ransohoff R, Perry V . Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009; 27:119-45. DOI: 10.1146/annurev.immunol.021908.132528. View

Quan N . Immune-to-brain signaling: how important are the blood-brain barrier-independent pathways?. Mol Neurobiol. 2008; 37(2-3):142-52. PMC: 2780323. DOI: 10.1007/s12035-008-8026-z. View

Coles B, Fielding C, Rose-John S, Scheller J, Jones S, ODonnell V . Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo. Am J Pathol. 2007; 171(1):315-25. PMC: 1941613. DOI: 10.2353/ajpath.2007.061078. View

Mines M, Yuskaitis C, King M, Beurel E, Jope R . GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS One. 2010; 5(3):e9706. PMC: 2838793. DOI: 10.1371/journal.pone.0009706. View

Campbell I, Abraham C, Masliah E, Kemper P, Inglis J, Oldstone M . Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A. 1993; 90(21):10061-5. PMC: 47713. DOI: 10.1073/pnas.90.21.10061. View

Kelley K, Bluthe R, Dantzer R, Zhou J, Shen W, Johnson R . Cytokine-induced sickness behavior. Brain Behav Immun. 2003; 17 Suppl 1:S112-8. DOI: 10.1016/s0889-1591(02)00077-6. View

Mizuguchi H, Mizuno H, Yasukawa K, Ishiguro T, Fukui K, Imanaka T . Enhanced signal transduction by a directly fused protein of interleukin-6 and its receptor. J Biosci Bioeng. 2005; 91(3):299-304. DOI: 10.1263/jbb.91.299. View

10.

Jang S, Kelley K, Johnson R . Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A. 2008; 105(21):7534-9. PMC: 2396685. DOI: 10.1073/pnas.0802865105. View

11.

Sparkman N, Johnson R . Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation. 2008; 15(4-6):323-30. PMC: 2704383. DOI: 10.1159/000156474. View

12.

Godbout J, Berg B, Kelley K, Johnson R . alpha-Tocopherol reduces lipopolysaccharide-induced peroxide radical formation and interleukin-6 secretion in primary murine microglia and in brain. J Neuroimmunol. 2004; 149(1-2):101-9. DOI: 10.1016/j.jneuroim.2003.12.017. View

13.

Diehl S, Rincon M . The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 2002; 39(9):531-6. DOI: 10.1016/s0161-5890(02)00210-9. View

14.

Rose-John S, Heinrich P . Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J. 1994; 300 ( Pt 2):281-90. PMC: 1138158. DOI: 10.1042/bj3000281. View

15.

Godbout J, Chen J, Abraham J, Richwine A, Berg B, Kelley K . Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 2005; 19(10):1329-31. DOI: 10.1096/fj.05-3776fje. View

16.

Berg B, Godbout J, Chen J, Kelley K, Johnson R . alpha-Tocopherol and selenium facilitate recovery from lipopolysaccharide-induced sickness in aged mice. J Nutr. 2005; 135(5):1157-63. DOI: 10.1093/jn/135.5.1157. View

17.

Dantzer R, Bluthe R, Gheusi G, Cremona S, Laye S, Parnet P . Molecular basis of sickness behavior. Ann N Y Acad Sci. 1999; 856:132-138. DOI: 10.1111/j.1749-6632.1998.tb08321.x. View

18.

Jostock T, Mullberg J, Ozbek S, Atreya R, Blinn G, Voltz N . Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem. 2000; 268(1):160-7. DOI: 10.1046/j.1432-1327.2001.01867.x. View

19.

Marz P, Otten U, Rose-John S . Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors. Eur J Neurosci. 1999; 11(9):2995-3004. DOI: 10.1046/j.1460-9568.1999.00755.x. View

20.

Chen Q, Wang W, Bruce R, Li H, Schleider D, Mulbury M . Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity. 2004; 20(1):59-70. DOI: 10.1016/s1074-7613(03)00358-3. View