Constitutive and LPS-regulated expression of interleukin-18 receptor beta variants in the mouse brain

Abstract

Interleukin (IL)-18 is a pro-inflammatory cytokine that is proposed to be involved in physiological as well as pathological conditions in the adult brain. IL-18 acts through a heterodimer receptor comprised of a subunit alpha (IL-18Rα) required for binding, and a subunit beta (IL-18Rβ) necessary for activation of signal transduction. We recently demonstrated that the canonical alpha binding chain, and its putative decoy isoform, are expressed in the mouse central nervous system (CNS) suggesting that IL-18 may act on the brain by directly binding its receptor. Considering that the co-expression of the beta chain seems to be required to generate a functional receptor and, a short variant of this chain has been described in rat and human brain, in this study we have extended our investigation to IL-18Rβ in mouse. Using a multi-methodological approach we found that: (1) a short splice variant of IL-18Rβ was expressed in the CNS even if at lower levels compared to the full-length IL-18Rβ variants, (2) the canonical IL-18Rβ is expressed in the CNS particularly in areas and nuclei belonging to the limbic system as previously observed for IL-18Rα and finally (3) we have also demonstrated that both IL-18Rβ isoforms are up-regulated in different brain areas three hours after a single lipopolysaccharide (LPS) injection suggesting that IL-18Rβ in the CNS might be involved in mediating the endocrine and behavioral effects of LPS. Our data highlight the considerable complexity of the IL-18 regulation activity in the mouse brain and further support an important central role for IL-18.

Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice

“…Also consistent with a central mode of action, IL-18 receptor complex subunits are constitutively expressed in mouse hypothalamus (Alboni et al, 2009; Alboni et al, 2010; Alboni et al, 2011; Wheeler et al, 2000), notably in the paraventricular nucleus and ventromedial hypothalamic nucleus. Both the IL-18Rα and Rβ subunits also are present in the hindbrain, including the nucleus tractus solitarius.…”

“…IL-18 modulates neuronal activity (Cumiskey et al, 2007; Curran and O’Connor, 2001; Kanno et al, 2004) and is also centrally produced in medial habenula, cortex, striatum, and glia (Alboni et al, 2010; Conti et al, 1999; Culhane et al, 1998; Sugama et al, 2002). Peripheral immune challenge elicits the hypothalamic synthesis of IL-18 and its receptor, suggesting that central IL-18 activation might contribute to anorectic and metabolic components of the “sickness syndrome.” (Alboni et al, 2010; Alboni et al, 2011). …”

“…Both the IL-18Rα and Rβ subunits also are present in the hindbrain, including the nucleus tractus solitarius. The reviewed appetite-regulatory brain regions express not only the canonical IL-18Rs but also three additional isoforms predicted to be either decoy receptors or negative regulators of IL-18 action (Alboni et al, 2010; Alboni et al, 2011). Consistent with this distribution, here we found that central IL-18 administration also suppressed high-fat diet intake and did so via an IL-18R-dependent mechanism.…”

Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells

“…We previously demonstrated that IL-18Rs are expressed in the hippocampal neurons of the adult mouse (Alboni et al, 2009; Alboni et al, 2011a). Here, we investigated whether IL-18 could induce STAT3 phosphorylation in Tyr705 and Ser727 amino acid residues.…”

Diet, behavior and immunity across the lifespan

“…One of these isoforms, arbitrarily named IL-18Rα type II to distinguish it from the canonical Type I form, lacks the intracellular toll/interleukin receptor (TIR) domain required for activation of the IRAK pathway and was thus proposed to be a decoy receptor. A short splice variant of the IL-18Rβ, previously described in rat, where it was named short IL-18Rβ (sIL-18Rβ), also exists (Alboni et al , 2011). sIL-18Rβ is comprised of only one of the extracellular IgG domains of the receptor chain and it is thus believed to be a soluble form that can interfere with the dimerization of the canonical receptor complex.…”