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Blockade of CCN4 attenuates CCl4-induced liver fibrosis.

Li X, Chen Y, Ye W, Tao X, Zhu J, Wu S, Lou L - Arch Med Sci (2015)

Bottom Line: The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased.Treatment with CCN4mAb significantly inhibited CCl4-induced CCN4 expression, leading to attenuated CCl4-induced liver injury and the inflammatory response.CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Yiwu Central Hospital, Zhejiang, China.

ABSTRACT

Introduction: CCN4, also termed WNT-inducible signaling pathway protein-1 (WISP-1), has important roles in inflammation and tissue injury. This study aimed to investigate the effect of CCN4 inhibition using monoclonal anti-CCN4 antibody (CCN4mAb) on the liver injury and fibrosis in a mouse model of liver fibrosis.

Material and methods: The mouse liver fibrosis model was induced by carbon tetrachloride (CCl4). Mice received vehicle (saline/olive oil) by subcutaneous injection, CCl4 by subcutaneous injection or CCl4 (subcutaneous) plus CCN4mAb by subcutaneous injection. The pro-inflammatory and pro-fibrotic factors were determined by Western blot. The biochemistry and histopathology, collagen deposition and nuclear factor (NF)-κB activity were also assessed.

Results: Chronic CCl4 treatment caused liver injury and collagen accumulation. The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased. Treatment with CCN4mAb significantly inhibited CCl4-induced CCN4 expression, leading to attenuated CCl4-induced liver injury and the inflammatory response. CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1.

Conclusions: CCN4 inhibition by CCN4mAb in vivo significantly attenuated the CCl4-induced liver injury and the progression of liver fibrosis. CCN4 may represent a novel therapeutic target for liver injury and fibrosis.

No MeSH data available.


Related in: MedlinePlus

CCN4mAb treatment reduced the production of serum TNF-α, IL-6 and CCL2**P < 0.01, compared with vehicle-treated normal control; ##p < 0.01, compared with CCl4-treated group (n = 10–12/ group). 1: vehicle (saline/olive oil)-treated normal mice; 2: CCl4 by subcutaneous injection. 3: CCl4 plus CCN4mAb treatment. N = 12 mice per group.
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Figure 0004: CCN4mAb treatment reduced the production of serum TNF-α, IL-6 and CCL2**P < 0.01, compared with vehicle-treated normal control; ##p < 0.01, compared with CCl4-treated group (n = 10–12/ group). 1: vehicle (saline/olive oil)-treated normal mice; 2: CCl4 by subcutaneous injection. 3: CCl4 plus CCN4mAb treatment. N = 12 mice per group.

Mentions: Serum levels of TNF-α (90.8 ±17.4 vs. 241.4 ±18.1 vs. 112 ±13.0 pg/ml, p < 0.01), IL-6 (189 ±20.1 vs. 452.4 ±28.3 vs. 206.6 ±21.0, p < 0.01) and CCL2 (2097 ±149.5 vs. 9812.3 ±896.8 vs. 2301.4 ±202.5, p < 0.01) were significantly elevated by more than 3-fold respectively compared with the vehicle-treated control group) (Figure 4). Of note, group 3 showed markedly reduced serum levels of TNF-α, IL-6 and CCL2 (all p < 0.01), as indicated by ELISA. These data indicate that CCN4mAb treatment also significantly reduced the CCl4-induced inflammatory response.


Blockade of CCN4 attenuates CCl4-induced liver fibrosis.

Li X, Chen Y, Ye W, Tao X, Zhu J, Wu S, Lou L - Arch Med Sci (2015)

CCN4mAb treatment reduced the production of serum TNF-α, IL-6 and CCL2**P < 0.01, compared with vehicle-treated normal control; ##p < 0.01, compared with CCl4-treated group (n = 10–12/ group). 1: vehicle (saline/olive oil)-treated normal mice; 2: CCl4 by subcutaneous injection. 3: CCl4 plus CCN4mAb treatment. N = 12 mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 0004: CCN4mAb treatment reduced the production of serum TNF-α, IL-6 and CCL2**P < 0.01, compared with vehicle-treated normal control; ##p < 0.01, compared with CCl4-treated group (n = 10–12/ group). 1: vehicle (saline/olive oil)-treated normal mice; 2: CCl4 by subcutaneous injection. 3: CCl4 plus CCN4mAb treatment. N = 12 mice per group.
Mentions: Serum levels of TNF-α (90.8 ±17.4 vs. 241.4 ±18.1 vs. 112 ±13.0 pg/ml, p < 0.01), IL-6 (189 ±20.1 vs. 452.4 ±28.3 vs. 206.6 ±21.0, p < 0.01) and CCL2 (2097 ±149.5 vs. 9812.3 ±896.8 vs. 2301.4 ±202.5, p < 0.01) were significantly elevated by more than 3-fold respectively compared with the vehicle-treated control group) (Figure 4). Of note, group 3 showed markedly reduced serum levels of TNF-α, IL-6 and CCL2 (all p < 0.01), as indicated by ELISA. These data indicate that CCN4mAb treatment also significantly reduced the CCl4-induced inflammatory response.

Bottom Line: The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased.Treatment with CCN4mAb significantly inhibited CCl4-induced CCN4 expression, leading to attenuated CCl4-induced liver injury and the inflammatory response.CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Yiwu Central Hospital, Zhejiang, China.

ABSTRACT

Introduction: CCN4, also termed WNT-inducible signaling pathway protein-1 (WISP-1), has important roles in inflammation and tissue injury. This study aimed to investigate the effect of CCN4 inhibition using monoclonal anti-CCN4 antibody (CCN4mAb) on the liver injury and fibrosis in a mouse model of liver fibrosis.

Material and methods: The mouse liver fibrosis model was induced by carbon tetrachloride (CCl4). Mice received vehicle (saline/olive oil) by subcutaneous injection, CCl4 by subcutaneous injection or CCl4 (subcutaneous) plus CCN4mAb by subcutaneous injection. The pro-inflammatory and pro-fibrotic factors were determined by Western blot. The biochemistry and histopathology, collagen deposition and nuclear factor (NF)-κB activity were also assessed.

Results: Chronic CCl4 treatment caused liver injury and collagen accumulation. The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased. Treatment with CCN4mAb significantly inhibited CCl4-induced CCN4 expression, leading to attenuated CCl4-induced liver injury and the inflammatory response. CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1.

Conclusions: CCN4 inhibition by CCN4mAb in vivo significantly attenuated the CCl4-induced liver injury and the progression of liver fibrosis. CCN4 may represent a novel therapeutic target for liver injury and fibrosis.

No MeSH data available.


Related in: MedlinePlus