Anandamide Influences Interleukin-1β Synthesis and IL-1 System Gene Expressions in the Ovine Hypothalamus during Endo-Toxin-Induced Inflammation

SIMPLE SUMMARY: Pro-inflammatory cytokines are considered to be one of the most important mediators affecting the function of central nervous system during an immune/inflammatory challenge. It was found that in acting on different hypothalamic nuclei, pro-inflammatory cytokines influence the centrally regulated processes including reproduction. Recently, it has been shown that the endocannabinoid system and endogenous cannabinoids may attenuate the inflammatory response. Therefore, in our study we examined the influence of anandamide, one of the earliest known endocannabinoids, on the synthesis of interleukin (IL)-1β and IL-1 system gene expressions in the hypothalamic structures involved in gonadotropin-releasing hormone (GnRH)-ergic activity, and thus the central control of reproduction, during immune stress induced by endotoxin injection. It was found that anandamide inhibited lipopolysaccharide (LPS)-stimulated synthesis of IL-1β in the hypothalamus, likely affecting posttranscriptional levels of this cytokine synthesis. Anti-inflammatory effect of anandamide at the level of central nervous system might also result from its stimulating action on IL-1 antagonist and IL-1 type II receptor gene expression. This study suggests the potential of endocannabinoids and/or their metabolites in the inhibition of inflammatory process at the level of the central nervous system, as well as their usefulness in the therapy of inflammation-induced neuroendocrine disorders, but further detailed research is required to investigate this issue. ABSTRACT: This study evaluated the effect of anandamide (AEA) on interleukin (IL)-1β synthesis and gene expression of IL-1β, its type I (IL-1R1) and II (IL-1R2) receptors, and IL-1 receptor antagonist (IL-1RN) in the hypothalamic structures, involved in the central control of reproduction, during inflammation. Animals were intravenously (i.v.) injected with bacterial endotoxin-lipopolysaccharide (LPS) (400 ng/kg) or saline, and two hours after LPS administration., a third group received i.v. injection of AEA (10 μg/kg). Ewes were euthanized one hour later. AEA injection (p < 0.05) suppressed LPS-induced expression of IL-1β protein in the hypothalamus. The gene expression of IL-1β, IL-1RN, and IL-1R2 in the hypothalamic structures was higher (p < 0.05) in animals treated with both LPS and AEA in comparison to other experimental groups. AEA administration did not influence LPS-stimulated IL-1R1 gene expression. Our study shows that AEA suppressed IL-1β synthesis in the hypothalamus, likely affecting posttranscriptional levels of this cytokine synthesis. However, anti-inflammatory effect of AEA might also result from its stimulating action on IL-1RN and IL-1R2 gene expression. These results indicate the potential of endocannabinoids and/or their metabolites in the inhibition of inflammatory process at the level of central nervous system, and therefore their usefulness in the therapy of inflammation-induced neuroendocrine disorders.