Induction of Interleukin-1(beta) Converting Enzyme in the Brain and Its Role in Anorexia Induced by Centrally Administered Lipopolysaccharide

Precursor interleukin-1beta (IL-1beta) is cleaved by interleukin-1beta converting enzyme (ICE) to generate the biologically active form of IL-1beta. Interleukin-1beta synthesized in the brain is thought to be involved in the induction of sickness behavior by lipopolysaccharide (LPS). In the first study, the ability of LPS to induce ICE in microglia was examined. Determined by RT-PCR, ICE mRNA was constitutively expressed in murine microglia cell line N13 cells and primary microglia isolated from both endotoxin- responsive C3H/HeOuJ and endotoxin-resistant C3H/HeJ mice. Upon exposure to LPS, ICE mRNA levels were markedly elevated in N13 cells and in microglia from C3H/HeOuJ mice, but not in microglia from endotoxin-resistant C3H/HeJ mice. A modest increase in immunoreactivity for the p45 ICE precursor protein was evident in N13 cells and primary microglia from C3H/HeOuJ mice following exposure to LPS using Western immunoblotting. To evaluate if ICE in the brain is involved in anorexia induced by LPS, food intake was compared in wild type (WT) and ICE-deficient (ICE-/-) mice injected intracerebroventricularly (ICV) with LPS. LPS reduced food intake in a dose-dependent manner in WT mice. ICE-/- mice, however, were resistant to the anorectic effects of central LPS but responsive to anorectic properties of recombinant murine IL-1beta. While ICV injection of neither ICE-like protease cathepsin G nor LPS alone reduced food intake in ICE-/- mice, in combination, however, cathepsin G restored the anorectic properties of central LPS in ICE-/- mice. Conversely, in WT mice the decrease in food intake caused by central LPS was entirely blocked by prior treatment with the YVAD.CMK. Using in situ hybridization immunohistochemistry, a marked increase in ICE mRNA was evident after LPS in all brain areas examined, but the hippocampus and the dorsomedial hypothalamus comprised a dense population of cells expressing ICE mRNA. These results provide further support for the role of IL-1beta in LPS-induced anorexia and indicate ICE may be a viable pharmacological target for inhibiting this response.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Yao, Jianhua

Contributors dc:contributor

• Johnson, Rodney W.

• Biology, Animal Physiology

Language dc:language

eng

Identifier

(MiAaPQ)AAI9912433

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/83651