IL‐1β signalling in glial cells in wildtype and IL‐1RI deficient mice

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. 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‐1β in cultures derived from IL‐1RI−/− and wildtype mice, and to characterize the functional importance of IL‐1 signalling pathways in glia. IL‐1β induced marked release of IL‐6 and prostaglandin‐E 2 (PGE 2 ) in the culture medium, and activated nuclear factor‐kappa B (NFκB) 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. In wildtype mice, inhibition of p38 or ERK1/2 MAPKs significantly reduced IL‐1β induced IL‐6 release, whilst the NFκB inhibitor caffeic acid phenethyl ester (CAPE) modulated IL‐1 induced IL‐6 release by action on NFκB and MAPKs pathways. These data demonstrate that IL‐1RI is essential for IL‐1β 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.British Journal of Pharmacology (2002) 136 , 312–320; doi: 10.1038/sj.bjp.0704715