title: RBM3 regulates temperature sensitive miR-142-5p and miR-143 (thermomiRs), which target immune genes and control fever.
abstract: Fever is commonly used to diagnose disease and is consistently associated with increased mortality in critically ill patients. However, the molecular controls of elevated body temperature are poorly understood. We discovered that the expression of RNA-binding motif protein 3 (RBM3), known to respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients with fever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C). Notably, RBM3 expression is reduced during fever whether or not infection is demonstrable. Reduced RBM3 expression resulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termed thermomiRs. ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogens including IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may be crucial to prevent pathological hyperthermia. Using normal PBMCs that were exogenously exposed to fever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3 were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h time course. Collectively, our results indicate the existence of a negative feedback loop that regulates fever via reduced RBM3 levels and increased expression of miR-142-5p and miR-143.
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Justin J-L
authors.initials: JJ
authors.lastname: Wong
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Amy Y M
authors.initials: AY
authors.lastname: Au
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia Bioinformatics Laboratory, Centenary Institute, Camperdown 2050, Australia.
authors.forename: Dadi
authors.initials: D
authors.lastname: Gao
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Pinello
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Chau-To
authors.initials: CT
authors.lastname: Kwok
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Annora
authors.initials: A
authors.lastname: Thoeng
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Lau
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Jane E A
authors.initials: JE
authors.lastname: Gordon
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schmitz
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Trung V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia Bioinformatics Laboratory, Centenary Institute, Camperdown 2050, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Middleton
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bailey
authors.affiliation: Sydney Medical School, University of Sydney, NSW 2006, Australia Origins of Cancer Program, Centenary Institute, Camperdown 2050, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown 2050, Australia j.rasko@centenary.usyd.edu.au.
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.affiliation: Gene & Stem Cell Therapy Program, Centenary Institute, Camperdown 2050, Australia Sydney Medical School, University of Sydney, NSW 2006, Australia Bioinformatics Laboratory, Centenary Institute, Camperdown 2050, Australia CNRS, UMR 5203, Montpellier 34094, France william.ritchie@igf.cnrs.fr.
authors.forename: William
authors.initials: W
authors.lastname: Ritchie
mesh_terms: D001831:Body Temperature; D001833:Body Temperature Regulation / Q000235:genetics; D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological; D005334:Fever / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C508600:IL6 protein, human; C494199:IL6ST protein, human; D015850:Interleukin-6; C555159:MIRN142 microRNA, human; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; C099506:RBM3 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D018078:Receptors, Prostaglandin E; C495342:TLR2 protein, human; C439524:TNF protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130
references.citation: Bioinformatics. 2012 Apr 15;28(8):1058-61
references.pmid: 22408193
references.citation: Med Oncol. 2014 Dec;31(12):319
references.pmid: 25412934
references.citation: Exp Mol Med. 2009 Sep 30;41(9):638-47
references.pmid: 19478556
references.citation: Trends Cell Biol. 2015 Mar;25(3):137-47
references.pmid: 25484347
references.citation: Biochem Biophys Res Commun. 2013 Sep 13;439(1):6-11
references.pmid: 23973710
references.citation: Int J Clin Pract. 2014 Apr;68(4):520-8
references.pmid: 24548627
references.citation: Blood. 2011 Apr 7;117(14):3720-32
references.pmid: 21304099
references.citation: J Transl Med. 2010;8:78
references.pmid: 20727170
references.citation: Nat Rev Mol Cell Biol. 2012 Apr;13(4):239-50
references.pmid: 22436747
references.citation: Cardiovasc Res. 2009 Jul 1;83(1):131-9
references.pmid: 19377067
references.citation: Cell. 1993 Feb 12;72(3):415-25
references.pmid: 7679328
references.citation: PLoS One. 2011;6(12):e28446
references.pmid: 22145045
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12792-7
references.pmid: 23858444
references.citation: Shock. 2012 Dec;38(6):620-9
references.pmid: 23143054
references.citation: EMBO Mol Med. 2012 Jul;4(7):617-32
references.pmid: 22367739
references.citation: Nature. 2001 Apr 26;410(6832):1099-103
references.pmid: 11323673
references.citation: Gene. 1999 Apr 29;231(1-2):59-65
references.pmid: 10231569
references.citation: Blood. 2011 Jun 9;117(23):6172-83
references.pmid: 21474672
references.citation: J Appl Physiol (1985). 2002 Jun;92(6):2648-55
references.pmid: 12015385
references.citation: Intensive Care Med. 2012 Jan 31;:null
references.pmid: 22290072
references.citation: Am J Physiol. 1976 Jul;231(1):198-203
references.pmid: 961860
references.citation: J Endotoxin Res. 2004;10(4):201-22
references.pmid: 15373964
references.citation: Nat Genet. 2002 Apr;30(4):363-4
references.pmid: 11896390
references.citation: Science. 1999 Jul 9;285(5425):260-3
references.pmid: 10398604
references.citation: World J Crit Care Med. 2012 Aug 04;1(4):106-22
references.pmid: 24701408
references.citation: Arthritis Res Ther. 2011;13(4):229
references.pmid: 21787439
references.citation: Mol Cell Biol. 1988 Jan;8(1):91-5
references.pmid: 3122028
references.citation: PLoS One. 2013;8(10):e75918
references.pmid: 24146790
references.citation: PLoS One. 2013;8(1):e54612
references.pmid: 23372743
references.citation: Blood. 2013 Feb 28;121(9):1563-73
references.pmid: 23293080
references.citation: Nat Methods. 2012 Apr;9(4):357-9
references.pmid: 22388286
references.citation: PLoS One. 2012;7(3):e33095
references.pmid: 22431998
references.citation: Cell Death Differ. 2015 Jan;22(1):22-33
references.pmid: 25190144
references.citation: Trends Mol Med. 2014 Apr;20(4):204-13
references.pmid: 24548661
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1865-70
references.pmid: 15684048
references.citation: Int Immunopharmacol. 2014 Nov;23(1):37-45
references.pmid: 25130606
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: RNA. 2007 May;13(5):723-30
references.pmid: 17400817
references.citation: J Infect Public Health. 2011 Aug;4(3):108-24
references.pmid: 21843857
references.citation: Sci Rep. 2013;3:2054
references.pmid: 23792593
references.citation: PLoS Pathog. 2013;9(6):e1003451
references.pmid: 23825948
references.citation: J Hematol Oncol. 2014;7:42
references.pmid: 24886830
references.citation: Blood. 2011 Jan 27;117(4):1205-17
references.pmid: 20956800
references.citation: Mol Cancer. 2013;12:77
references.pmid: 23866094
references.citation: Genomics Proteomics Bioinformatics. 2012 Oct;10(5):246-53
references.pmid: 23200134
references.citation: J Immunol Methods. 2009 May 31;344(2):109-15
references.pmid: 19345690
references.citation: Cell. 1986 Apr 25;45(2):185-93
references.pmid: 2421918
references.citation: Arthritis Rheum. 2012 Sep;64(9):2953-63
references.pmid: 22549634
references.citation: Stroke. 2008 Nov;39(11):3029-35
references.pmid: 18723420
references.citation: Cell Rep. 2014 Jun 12;7(5):1362-70
references.pmid: 24857664