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Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model.

Kessler SP, Obery DR, de la Motte C - Int J Cell Biol (2015)

Bottom Line: Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD).Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation.Our data suggest, HAS3 plays a crucial role in driving gut inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, Lerner Research Institute Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 mice are protected from colitis, compared to wild-type and HAS1 mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

No MeSH data available.


Related in: MedlinePlus

Serum IL-6 in DSS-treated mice. Serum isolated from all mice was tested for IL-6 in an ELISA format, normalized by protein concentration in the serum sample by Bradford assay to determine the ng IL-6/ug total serum protein. Bars represent the average of mice of the same genotype at the indicated time point. Error bars reflect ±SEM. Comparison of  mice to wild-type mice at the indicated time point: ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005 at 95% confidence.
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fig4: Serum IL-6 in DSS-treated mice. Serum isolated from all mice was tested for IL-6 in an ELISA format, normalized by protein concentration in the serum sample by Bradford assay to determine the ng IL-6/ug total serum protein. Bars represent the average of mice of the same genotype at the indicated time point. Error bars reflect ±SEM. Comparison of mice to wild-type mice at the indicated time point: ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005 at 95% confidence.

Mentions: Elevated levels of the inflammatory cytokine IL-6 have been documented in IBD patients and in experimental mice treated with DSS [26, 27]. To test whether the decreased DAI and retention of body weight observed in HAS3 mice were also accompanied by a change in circulating IL-6 levels, we collected serum from all mice on the day of sacrifice by cardiac puncture. Serum IL-6 levels, measured in an ELISA format and normalized for total protein concentration, are presented in Figure 4. We observed that the HAS3 mice possessed the lowest amount of circulating IL-6 at all time points we tested, but especially at day 7, compared to wild-type mice (P < 0.005). At day 7, IL-6 levels in the HAS3 mice were barely detectable, whereas wild-type, HAS1 , and HAS1/3 double mice all have elevated circulating IL-6 in the 1.0–2.5 ng/mg range. Interestingly, the HAS1/HAS3 mice had the highest level of IL-6, even surpassing levels found in wild-type mice at each time point.


Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model.

Kessler SP, Obery DR, de la Motte C - Int J Cell Biol (2015)

Serum IL-6 in DSS-treated mice. Serum isolated from all mice was tested for IL-6 in an ELISA format, normalized by protein concentration in the serum sample by Bradford assay to determine the ng IL-6/ug total serum protein. Bars represent the average of mice of the same genotype at the indicated time point. Error bars reflect ±SEM. Comparison of  mice to wild-type mice at the indicated time point: ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005 at 95% confidence.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581575&req=5

fig4: Serum IL-6 in DSS-treated mice. Serum isolated from all mice was tested for IL-6 in an ELISA format, normalized by protein concentration in the serum sample by Bradford assay to determine the ng IL-6/ug total serum protein. Bars represent the average of mice of the same genotype at the indicated time point. Error bars reflect ±SEM. Comparison of mice to wild-type mice at the indicated time point: ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005 at 95% confidence.
Mentions: Elevated levels of the inflammatory cytokine IL-6 have been documented in IBD patients and in experimental mice treated with DSS [26, 27]. To test whether the decreased DAI and retention of body weight observed in HAS3 mice were also accompanied by a change in circulating IL-6 levels, we collected serum from all mice on the day of sacrifice by cardiac puncture. Serum IL-6 levels, measured in an ELISA format and normalized for total protein concentration, are presented in Figure 4. We observed that the HAS3 mice possessed the lowest amount of circulating IL-6 at all time points we tested, but especially at day 7, compared to wild-type mice (P < 0.005). At day 7, IL-6 levels in the HAS3 mice were barely detectable, whereas wild-type, HAS1 , and HAS1/3 double mice all have elevated circulating IL-6 in the 1.0–2.5 ng/mg range. Interestingly, the HAS1/HAS3 mice had the highest level of IL-6, even surpassing levels found in wild-type mice at each time point.

Bottom Line: Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD).Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation.Our data suggest, HAS3 plays a crucial role in driving gut inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, Lerner Research Institute Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 mice are protected from colitis, compared to wild-type and HAS1 mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

No MeSH data available.


Related in: MedlinePlus