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The UII/UT system mediates upregulation of proinflammatory cytokines through p38 MAPK and NF-κB pathways in LPS-stimulated Kupffer cells.

Liu LM, Liang DY, Ye CG, Tu WJ, Zhu T - PLoS ONE (2015)

Bottom Line: The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β).Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs.Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatology, Songjiang Hospital Affiliated to the First People's Hospital Shanghai Jiaotong University, Shanghai, China.

ABSTRACT
The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor κB (NF-κB) p65 subunit in KCs and enhanced the binding activity of NF-κB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.

No MeSH data available.


Related in: MedlinePlus

Expression of the nucleus NF-κB p65 subunit in various groups of primary KCs.Left panel shows a representative picture of Western blot, and right shows the relative levels of p65 protein in KCs after normalization to histone. Lane 1: UII(-)urantide(-)LPS(-); Lane 2: UII(+)urantide(-)LPS(-); Lane 3: UII(-)urantide(+)LPS(-); Lane 4: UII(-)urantide(-)LPS(+); Lane 5: UII(+)urantide(-)LPS(+); Lane 6: UII(-)urantide(+)LPS(+). Bars represent means ± SD (n = 6). *P<0.05 and ** P<0.01 versus control cells [UII(-)urantide(-)LPS(-)]; #P<0.05 and ##P<0.01 versus LPS-stimulated cells [UII(-)urantide(-)LPS(+)]
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pone.0121383.g006: Expression of the nucleus NF-κB p65 subunit in various groups of primary KCs.Left panel shows a representative picture of Western blot, and right shows the relative levels of p65 protein in KCs after normalization to histone. Lane 1: UII(-)urantide(-)LPS(-); Lane 2: UII(+)urantide(-)LPS(-); Lane 3: UII(-)urantide(+)LPS(-); Lane 4: UII(-)urantide(-)LPS(+); Lane 5: UII(+)urantide(-)LPS(+); Lane 6: UII(-)urantide(+)LPS(+). Bars represent means ± SD (n = 6). *P<0.05 and ** P<0.01 versus control cells [UII(-)urantide(-)LPS(-)]; #P<0.05 and ##P<0.01 versus LPS-stimulated cells [UII(-)urantide(-)LPS(+)]

Mentions: We also examined the expression of nuclear NF-κB p65 protein in KCs. The results showed that KCs treated with UII alone or treated with urantide did not show statistically significant differences in nuclear p65 protein compared with that of the normal control group, whereas the level of nuclear p65 protein was significantly increased after LPS treatment (P<0.01 versus control cells). Pretreatment with urantide significantly inhibited the LPS-stimulated p65 protein expression in KCs (P<0.01 versus LPS-stimulated cells) (Fig. 6).


The UII/UT system mediates upregulation of proinflammatory cytokines through p38 MAPK and NF-κB pathways in LPS-stimulated Kupffer cells.

Liu LM, Liang DY, Ye CG, Tu WJ, Zhu T - PLoS ONE (2015)

Expression of the nucleus NF-κB p65 subunit in various groups of primary KCs.Left panel shows a representative picture of Western blot, and right shows the relative levels of p65 protein in KCs after normalization to histone. Lane 1: UII(-)urantide(-)LPS(-); Lane 2: UII(+)urantide(-)LPS(-); Lane 3: UII(-)urantide(+)LPS(-); Lane 4: UII(-)urantide(-)LPS(+); Lane 5: UII(+)urantide(-)LPS(+); Lane 6: UII(-)urantide(+)LPS(+). Bars represent means ± SD (n = 6). *P<0.05 and ** P<0.01 versus control cells [UII(-)urantide(-)LPS(-)]; #P<0.05 and ##P<0.01 versus LPS-stimulated cells [UII(-)urantide(-)LPS(+)]
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4372515&req=5

pone.0121383.g006: Expression of the nucleus NF-κB p65 subunit in various groups of primary KCs.Left panel shows a representative picture of Western blot, and right shows the relative levels of p65 protein in KCs after normalization to histone. Lane 1: UII(-)urantide(-)LPS(-); Lane 2: UII(+)urantide(-)LPS(-); Lane 3: UII(-)urantide(+)LPS(-); Lane 4: UII(-)urantide(-)LPS(+); Lane 5: UII(+)urantide(-)LPS(+); Lane 6: UII(-)urantide(+)LPS(+). Bars represent means ± SD (n = 6). *P<0.05 and ** P<0.01 versus control cells [UII(-)urantide(-)LPS(-)]; #P<0.05 and ##P<0.01 versus LPS-stimulated cells [UII(-)urantide(-)LPS(+)]
Mentions: We also examined the expression of nuclear NF-κB p65 protein in KCs. The results showed that KCs treated with UII alone or treated with urantide did not show statistically significant differences in nuclear p65 protein compared with that of the normal control group, whereas the level of nuclear p65 protein was significantly increased after LPS treatment (P<0.01 versus control cells). Pretreatment with urantide significantly inhibited the LPS-stimulated p65 protein expression in KCs (P<0.01 versus LPS-stimulated cells) (Fig. 6).

Bottom Line: The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β).Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs.Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatology, Songjiang Hospital Affiliated to the First People's Hospital Shanghai Jiaotong University, Shanghai, China.

ABSTRACT
The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor κB (NF-κB) p65 subunit in KCs and enhanced the binding activity of NF-κB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.

No MeSH data available.


Related in: MedlinePlus