Advanced SearchSearch Tips
An inhibitory alternative splice isoform of Toll-like receptor 3 is induced by type I interferons in human astrocyte cell lines
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
  • Journal title : BMB Reports
  • Volume 48, Issue 12,  2015, pp.696-701
  • Publisher : Korean Society for Biochemistry and Molecular Biology
  • DOI : 10.5483/BMBRep.2015.48.12.106
 Title & Authors
An inhibitory alternative splice isoform of Toll-like receptor 3 is induced by type I interferons in human astrocyte cell lines
Seo, Jin-Won; Yang, Eun-Jeong; Kim, Se Hoon; Choi, In-Hong;
  PDF(new window)
Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA. It stimulates pro-inflammatory cytokine and interferon production. Here we reported the expression of a novel isoform of TLR3 in human astrocyte cell lines whose message is generated by alternative splicing. The isoform represents the N-terminus of the protein. It lacks many of the leucine-rich repeat domains, the transmembrane domain, and the intracellular Toll/interleukin-1 receptor domain of TLR3. Type I interferons (interferon-α and interferon-β) induced the expression of this isoform. Exogenous overexpression of this isoform inhibited interferon regulatory factor 3, signal transducers and activators of transcription 1, and Inhibitor of kappa B α signaling following stimulation. This isoform of TLR3 also inhibited the production of chemokine interferon-γ-inducible protein 10. Our study clearly demonstrated that the expression of this isoform of TLR3 was a negative regulator of signaling pathways and that it was inducible by type I interferons. We also found that this isoform could modulate inflammation in the brain.
Astrocyte;Interferon;Isoform;Negative regulation;TLR3;
 Cited by
Matsumoto M, Oshiumi H and Seya T (2011) Antiviral responses induced by the TLR3 pathway. Rev Med Virol 21, 67-77 crossref(new window)

Hosokawa Y, Hosokawa I, Shindo S, Ozaki K and Matsuo T (2013) TLR3 agonist enhances CC chemokine ligand 20 production in IL-1beta-stimulated human gingival fibroblasts. Cell Immunol 283, 8-11 crossref(new window)

Yu M and Levine SJ (2011) Toll-like receptor, RIG-I-like receptors and the NLRP3 inflammasome: key modulators of innate immune responses to double-stranded RNA viruses. Cytokine Growth Factor Rev 22, 63-72 crossref(new window)

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F and Meinl E (2005) Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol 159, 12-19 crossref(new window)

Olson JK and Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173, 3916-3924 crossref(new window)

Matsumoto M, Funami K, Tanabe M et al (2003) Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 171, 3154-3162 crossref(new window)

Town T, Jeng D, Alexopoulou L, Tan J and Flavell RA (2006) Microglia recognize double-stranded RNA via TLR3. J Immunol 176, 3804-3812 crossref(new window)

Suh HS, Brosnan CF and Lee SC (2009) Toll-like receptors in CNS viral infections. Curr Top Microbiol Immunol 336, 63-81

Galic MA, Riazi K, Henderson AK, Tsutsui S and Pittman QJ (2009) Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats. Neurobiol Dis 36, 343-351 crossref(new window)

Riazi K, Galic MA and Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89, 34-42 crossref(new window)

Dakovic I, da Graca Andrada M, Folha T et al (2014) Clinical features of cerebral palsy in children with symptomatic congenital cytomegalovirus infection. Eur J Paediatr Neurol 18, 618-623 crossref(new window)

Singh TD, Fugate JE, Hocker SE and Rabinstein AA (2015) Postencephalitic epilepsy: clinical characteristics and predictors. Epilepsia 56, 133-138 crossref(new window)

Wilson JC, Toovey S, Jick SS and Meier CR (2014) Previously diagnosed influenza infections and the risk of developing epilepsy. Epidemiol Infect, 1-8

Sofroniew MV and Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119, 7-35 crossref(new window)

Le OT, Nguyen TT and Lee SY (2014) Phosphoinositide turnover in Toll-like receptor signaling and trafficking. BMB Rep 47, 361-368 crossref(new window)

Costello DA and Lynch MA (2013) Toll-like receptor 3 activation modulates hippocampal network excitability, via glial production of interferon-beta. Hippocampus 23, 696-707 crossref(new window)

Pan LN, Zhu W, Li Y et al (2014) Astrocytic Toll-like receptor 3 is associated with ischemic preconditioning-induced protection against brain ischemia in rodents. PLoS One 9, e99526 crossref(new window)

Nakajima A, Ibi D, Nagai T, Yamada S, Nabeshima T and Yamada K (2014) Induction of interferon-induced transmembrane protein 3 gene expression by lipopolysaccharide in astrocytes. Eur J Pharmacol 745, 166-175 crossref(new window)

Kim H, Yang E, Lee J et al (2008) Double-stranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes. Immunology 124, 480-488 crossref(new window)

Yang E, Shin JS, Kim H et al (2004) Cloning of TLR3 isoform. Yonsei Med J 45, 359-361 crossref(new window)

Sepulveda FE, Maschalidi S, Colisson R et al (2009) Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 31, 737-748 crossref(new window)

Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6, 823-835 crossref(new window)

Krieg AM and Vollmer J (2007) Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev 220, 251-269 crossref(new window)

Chockalingam A, Cameron JL, Brooks JC and Leifer CA (2011) Negative regulation of signaling by a soluble form of toll-like receptor 9. Eur J Immunol 41, 2176-2184 crossref(new window)

Ewald SE, Engel A, Lee J, Wang M, Bogyo M and Barton GM (2011) Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp Med 208, 643-651 crossref(new window)

Manoury B (2011) TLR9 regulation by proteolysis: a friend or a foe. Eur J Immunol 41, 2142-2144 crossref(new window)

Miranda-Hernandez S and Baxter AG (2013) Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol 2, 75-93

Touil T, Fitzgerald D, Zhang GX, Rostami A and Gran B (2006) Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J Immunol 177, 7505-7509 crossref(new window)

Murakami Y, Fukui R, Motoi Y et al (2014) Roles of the cleaved N-terminal TLR3 fragment and cell surface TLR3 in double-stranded RNA sensing. J Immunol 193, 5208-5217 crossref(new window)

Garcia-Cattaneo A, Gobert FX, Muller M et al (2012) Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling. Proc Natl Acad Sci U S A 109, 9053-9058 crossref(new window)

Toscano F, Estornes Y, Virard F et al (2013) Cleaved/associated TLR3 represents the primary form of the signaling receptor. J Immunol 190, 764-773 crossref(new window)

Qi R, Singh D and Kao CC (2012) Proteolytic processing regulates Toll-like receptor 3 stability and endosomal localization. J Biol Chem 287, 32617-32629 crossref(new window)