Mice deficient in interleukin-1 beta converting enzyme resist anorexia induced by central lipopolysaccharide

Interleukin-1 beta (IL-1 beta) is expressed in the mouse brain after intrac erebroventricular injection of lipopolysaccharide (LPS) and is thought to b e responsible for many of the behavioral and neuroendocrine changes that oc cur during inflammation. In this study we show that LPS in the brain also i nduces expression of interleukin-1 beta converting enzyme (ICE) and that IC E is important for the characteristic anorectic response of mice to intrace rebroventricular LPS. Specifically, mice that were deficient in ICE (ICE-/- ) resisted the anorexia caused by intracerebroventricular injection of LPS but were sensitive to the anorectic properties of recombinant IL-1 beta. Th e typical anorectic response seen in wild-type (WT) mice after LPS was rest ored in ICE-/- mice by intracerebroventricular administration of the ICE an alog cathepsin G. Conversely, anorexia induced by intracerebroventricular i njection of LPS in WT mice was blocked by prior intracerebroventricular inj ection of the ICE antagonist YVAD.CMK. Furthermore, in situ hybridization i mmunohistochemistry revealed intense expression of ICE mRNA in the hippocam pus and dorsomedial hypothalamus of WT mice after intracerebroventricular i njection of LPS. Thus ICE mRNA is expressed in brain after intracerebrovent ricular injection of LPS and is important for induction of anorexia, presum ably because it generates mature IL-1 beta. These results suggest that prev enting generation of mature IL-1 beta can inhibit anorexia induced by LPS i n the brain and, therefore, reveal ICE as a potential target for regulating food intake during brain inflammation.