title: Role for monokines in the metabolic effects of endotoxin. Interferon-gamma restores responsiveness of C3H/HeJ mice in vivo.
abstract: To examine the role of cytokines in mediating the lipogenic effects of endotoxin (LPS), we studied the effects of LPS and cytokines on hepatic fatty acid synthesis in LPS-sensitive C3H/OuJ mice and in LPS-resistant C3H/HeJ mice, whose macrophages are defective in the ability to produce tumor necrosis factor (TNF) and IL-1 in response to LPS. HeJ mice were 16-fold less sensitive than OuJ mice to the lipogenic effect of LPS. In OuJ mice, 10 micrograms of LPS caused a maximal increase in hepatic lipogenesis (3.86 +/- 0.41-fold), whereas in HeJ mice the maximal increase was only 1.79 +/- 0.32-fold after 100 micrograms of LPS. This lipogenic response paralleled the decreased ability of LPS to increase hepatic and splenic levels of mRNAs for TNF and IL-1 and serum levels of TNF in HeJ mice. In contrast, the maximal effect of TNF on lipogenesis was greater and the sensitivity to TNF was increased 2.4-fold in HeJ mice compared to OuJ mice. Administration of IFN-gamma before LPS in HeJ mice had no effect on IL-1 mRNA, but partially restored the LPS-induced increase in hepatic and splenic mRNA for TNF and serum TNF levels, which may account for the partial restoration of sensitivity to the lipogenic effect of LPS after IFN-gamma treatment. These results indicate that cytokines produced by mononuclear leukocytes mediate the lipogenic effects of LPS.
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: S
authors.initials: S
authors.lastname: Adi
authors.forename: A S
authors.initials: AS
authors.lastname: Pollock
authors.forename: J K
authors.initials: JK
authors.lastname: Shigenaga
authors.forename: A H
authors.initials: AH
authors.lastname: Moser
authors.forename: K R
authors.initials: KR
authors.lastname: Feingold
authors.forename: C
authors.initials: C
authors.lastname: Grunfeld
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis; D015870:Gene Expression; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D015846:Monokines / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D004731:Endotoxins; D005227:Fatty Acids; D007375:Interleukin-1; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma