IL-1 beta signalling in glial cells in wildtype and IL-1RI deficient mice.
1. Interleukin-1 (IL-1) has been implicated in neurodegeneration and in central nervous system (CNS)-mediated host defence responses to inflammation. All actions of IL-1 identified to date appear to be mediated through its only known functional type I receptor (IL-1RI). However, our recent evidence suggests that some actions of IL-1 in the brain may be IL-1RI independent, suggesting the involvement of a new, hitherto unknown functional receptor for IL-1. 2. The objective of the present study was to determine if primary mixed glial cells express additional functional IL-1 receptors by studying the signalling mechanisms responsible for the pro-inflammatory actions of IL-1beta in cultures derived from IL-1RI-/- and wildtype mice, and to characterize the functional importance of IL-1 signalling pathways in glia. 3. IL-1beta induced marked release of IL-6 and prostaglandin-E(2) (PGE(2)) in the culture medium, and activated nuclear factor-kappa B (NFkappaB) and the mitogen-activated protein kinases (MAPK) p38, c-Jun N-terminal kinase (JNK) and the extracellular signal-regulated protein kinase (ERK1/2) in cells from wildtype mice. These responses were dependent on IL-1RI, since cells isolated from IL-1R1-/- mice did not demonstrate any of these responses. 4. In wildtype mice, inhibition of p38 or ERK1/2 MAPKs significantly reduced IL-1beta induced IL-6 release, whilst the NFkappaB inhibitor caffeic acid phenethyl ester (CAPE) modulated IL-1 induced IL-6 release by action on NFkappaB and MAPKs pathways. 5. These data demonstrate that IL-1RI is essential for IL-1beta signalling in cultured mixed glial cells. Thus IL-1 actions observed in IL-1RI-/- mice in vivo may occur via an alternative pathway and/or via different CNS cells.
Parker
Lisa C
LC
School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, U.K.
Luheshi
Giamal N
GN
Rothwell
Nancy J
NJ
Pinteaux
Emmanuel
E
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053573:Receptors, Interleukin-1 Type I
D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D015232:Dinoprostone