Effects of urotensin-II on cytokines in early acute liver failure in mice

Abstract

Aim: To investigate urotensin-II (UII) and its effects on tumor necrosis factor (TNF)-α and interleukin (IL)-1β in early acute liver failure (ALF).

Methods: We investigated the time-dependent alteration in UII levels and its effects on TNF-α and IL-1β in liver and blood in the early stage of lipopolysaccharide/D-galactosamine-induced ALF.

Results: After lipopolysaccharide/D-galactosamine challenge, UII rose very rapidly and reached a maximal level 0.5 h, and the level remained significantly elevated after 2 h (P < 0.05). Six hours after challenge, UII began to degrade, but remained higher than at 0 h (P < 0.05). Pretreatment with urantide, an inhibitor of the UII receptor, suppressed the degree of UII increase in liver and blood at 6 h after challenge (P < 0.05 vs paired controls). In addition, liver and blood TNF-α increased from 1 to 6 h, and reached a peak at 1 and 2 h, respectively; however, IL-1β did not rise until 6 h after challenge. Urantide pretreatment inhibited the degree of TNF-α and IL-1β increase following downregulation of UII post-challenge (all P < 0.05).

Conclusion: UII plays a role in the pathogenesis and priming of ALF by triggering an inflammatory cascade and driving the early release of cytokines in mice.

Keywords: Acute hepatic failure; Interleukin-1β; Mouse; Tumor necrosis factor α; Urantide; Urotensin-II.

Figure 1

Time-dependent expression of urotensin-II in the early stage of lipopolysaccharide/D-galactosamine challenge in mice with or without urantide treatment. A: Representative ethidium bromide-stained gel of reverse transcription-PCR products from liver (M: DNA marker; Lines 1, 2, 3, 4, and 5: 0.0, 0.5, 1.0, 2.0, and 6.0 h after LPS/D-GalN challenge, respectively); B: Relative expression levels of UII mRNA in the liver (normalized to β-actin); C: Levels of UII secretion in blood as assayed by ELISA. Values are mean ± standard deviation (n = 6); ^aP < 0.05 vs 0 h; ^cP < 0.05 vs 6 h; ^eP < 0.05 vs mice without urantide pretreatment. UII: Urotensin-II; LPS: Lipopolysaccharide; D-GalN: D-galactosamine.

Figure 2

Time-dependent expression of tumor necrosis factor-α in the early stage of lipopolysaccharide/D-galactosamine challenge in mice with or without urantide pretreatment. A: Representative ethidium bromide-stained gel of reverse transcription-PCR products from liver (M: DNA marker; Lines 1, 2, 3, 4, and 5: 0.0, 0.5, 1.0, 2.0, and 6.0 h after LPS/D-GalN challenge, respectively); B: Relative expression levels of TNF-α mRNA in the liver (normalized to β-actin); C: Levels of TNF-α secretion in blood as assayed by ELISA. Values are mean ± standard deviation (n = 6); ^aP < 0.05 vs 0 h; ^cP < 0.05 vs 6 h; ^eP < 0.05 vs mice without urantide pretreatment. TNF: Tumor necrosis factor; LPS: Lipopolysaccharide; D-GalN: D-galactosamine.

Figure 3

Time-dependent expression of interleukin-1β in the early stage of lipopolysaccharide/D-galactosamine challenge in mice with or without urantide pretreatment. A: Representative ethidium bromide-stained gel of reverse transcription-PCR products in liver (M: DNA marker; Lines 1, 2, 3, 4, and 5: 0.0, 0.5, 1.0, 2.0, and 6.0 h after LPS/D-GalN challenge, respectively); B: Relative expression levels of IL-1β mRNA in the liver (normalized to β-actin); C: Levels of IL-1β secretion in blood as assayed by ELISA. Values are mean ± standard deviation (n = 6); ^aP < 0.05 vs 0 h; ^cP < 0.05 vs 6 h; ^eP < 0.05 vs mice without urantide pretreatment. IL: Interleukin; LPS: Lipopolysaccharide; D-GalN: D-galactosamine.