Interleukin-1beta system (ligand, receptor type I, receptor accessory protein and receptor antagonist), TNF-alpha, TGF-beta1 and neuropeptide Y mRNAs in specific brain regions during bacterial LPS-induced anorexia.

Bacterial lipopolysaccharide (LPS) or endotoxin induces neurological manifestations including anorexia. It is proposed that LPS-induced cytokine production is involved in the generation of neurological manifestations and in neuroinflammatory/immunological responses during gram-negative infections. For example, LPS-induced effects can be blocked or ameliorated by the interleukin-1 receptor antagonist (IL-1Ra). Here, sensitive and specific RNase protection assays were used to investigate the effects of the intracerebroventricular (i.c.v.) administration of LPS on mRNA levels of interleukin-1beta (IL-1beta) system components, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and neuropeptide Y (NPY) in the cerebellum, hippocampus, and hypothalamus. The same brain region sample was analyzed with all of the antisense probes. The data show simultaneous local induction of multiple cytokine components messenger ribonucleic acids (mRNAs) within specific brain regions in anorectic rats responding to i.c.v. administered LPS (500 ng/rat). Interleukin-1beta and IL-1Ra had a similar mRNA induction profile (hypothalamus > cerebellum > hippocampus). Interleukin-1 receptor type I (IL-1RI) mRNA also increased in all three brain regions examined, and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA was induced in the hypothalamus. Tumor necrosis factor-alpha mRNA levels increased in the hypothalamus > hippocampus > cerebellum. Levels of membrane bound IL-1R AcP, TGF-beta1, and NPY mRNAs did not change significantly in any brain region. The results suggest that: (1) endogenous up-regulation of IL-1beta and TNF-alpha in the hypothalamus contribute to LPS-induced anorexia; and (2) the ratio IL-1Ra/IL-1beta, and IL-1beta <--> TNF-alpha interactions may have implications for gram-negative infections associated with high levels of LPS in the brain-cerebrospinal fluid.