Gene regulation by IL-1beta independent of IL-1R1 in the mouse brain.
Interleukin-1 (IL-1) is a key pro-inflammatory cytokine that has diverse actions in the brain as a regulator of host defense responses and a mediator of inflammation. Two major agonists, IL-1alpha and IL-1beta, bind to a single known functional type-1 IL-1 receptor (IL-1RI) that associates with the accessory protein (IL-1RAcP), resulting in signal transduction. However, recent evidence suggests that some actions of IL-1 in the brain may be independent of IL-1R1 and the classical IL-1 signaling pathways, pointing to an as-yet unidentified functional receptor for IL-1. In this study, we have used cDNA microarray-based gene expression profiling to identify the possible genes induced by IL-1beta independently of IL-1R1. IL-1beta induced potential changes (greater than 2-fold vs. vehicle-treated) in the expression of up to 1285 candidate genes in wild-type primary mixed glia, and 404 candidate genes in IL-1R1-/- cells of the same type. Real-time quantitative polymerase chain reaction (PCR) on selected genes revealed that pentraxin-3, was upregulated by IL-1beta in wild-type, but not in IL-1R1-/- mixed glia. Amongst the other genes for which expression was modified by IL-1beta in IL-1R1-/- cells, we selected alpha-syntrophin and demonstrated by real-time quantitative PCR that expression of this gene is significantly downregulated by IL-1beta in primary mixed glia prepared from wild-type, IL-1R1-/-, IL-1RAcP-/- or MyD88-/- mice. In contrast, IL-1alpha fails to downregulate alpha-syntrophin expression in wild-type or IL-1R1-/- mixed glia. These results show that IL-1beta exclusively downregulates alpha-syntrophin expression independently of IL-1R1, and suggest the expression of additional functional IL-1 receptors in the CNS.
Andre
Ralph
R
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Moggs
Jonathan G
JG
Kimber
Ian
I
Rothwell
Nancy J
NJ
Pinteaux
Emmanuel
E
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D052160:Benzothiazoles; D001923:Brain Chemistry / Q000235:genetics*; D002097:C-Reactive Protein / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003959:Diamines; D015536:Down-Regulation / Q000502:physiology; D049029:Dystrophin-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D007375:Interleukin-1 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D020411:Oligonucleotide Array Sequence Analysis; D009930:Organic Chemicals / Q000378:metabolism; D011804:Quinolines; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000683:Serum Amyloid P-Component / Q000096:biosynthesis / Q000235:genetics; D000099153:Pentraxins
D048868:Adaptor Proteins, Signal Transducing; D052160:Benzothiazoles; D002097:C-Reactive Protein; D018076:DNA, Complementary; D003959:Diamines; D049029:Dystrophin-Associated Proteins; D007375:Interleukin-1; D053594:Myeloid Differentiation Factor 88; D009930:Organic Chemicals; D011804:Quinolines; D017472:Receptors, Interleukin-1; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C507780:Myd88 protein, mouse; C091824:syntrophin; C098022:SYBR Green I