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Mar Drugs
2019 Oct 31;1711:. doi: 10.3390/md17110622.
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Echinochrome A Reduces Colitis in Mice and Induces In Vitro Generation of Regulatory Immune Cells.
Oh SJ
,
Seo Y
,
Ahn JS
,
Shin YY
,
Yang JW
,
Kim HK
,
Han J
,
Mishchenko NP
,
Fedoreyev SA
,
Stonik VA
,
Kim HS
.
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Echinochrome A (Ech A), a natural pigment extracted from sea urchins, is the active ingredient of a marine-derived pharmaceutical called ''histochrome''. Since it exhibits several biological activities including anti-oxidative and anti-inflammatory effects, it has been applied to the management of cardiac injury and ocular degenerative disorders in Russia and its protective role has been studied for other pathologic conditions. In the present study, we sought to investigate the therapeutic potential of Ech A for inflammatory bowel disease (IBD) using a murine model of experimental colitis. We found that intravenous injection of Ech A significantly prevented body weight loss and subsequent lethality in colitis-induced mice. Interestingly, T cell proliferation was significantly inhibited upon Ech A treatment in vitro. During the helper T (Th) cell differentiation process, Ech A stimulated the generation regulatory T (Treg) cells that modulate the inflammatory response and immune homeostasis. Moreover, Ech A treatment suppressed the in vitro activation of pro-inflammatory M1 type macrophages, while inducing the production of M2 type macrophages that promote the resolution of inflammation and initiate tissue repair. Based on these results, we suggest that Ech A could provide a beneficial impact on IBD by correcting the imbalance in the intestinal immune system.
Figure 1. Echinochrome A (Ech A) administration provided therapeutic effects on DSS-induced colitis mice in a dose-dependent manner. (A) Body weight and survival rate monitoring results are shown. The body weight at day 0 considered was as 100%. Numbers in parentheses represent the percentage of dead mice. (B) Disease activity index score for colitis severity at day 12 was significantly reduced in the E10 group. (C) Colon length measurement results showing the protective role of Ech A against DSS-induced colonic damage. (D) The histopathological score of the colitis-affected and normal colon was evaluated with H&E stained tissue section. In total, six animals per group were used. Results are shown as mean ± SD. In (B) and (C), p-value significance was calculated by comparing other groups against the (+) group (marked as +). * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 2. Ech A impact on mixed lymphocyte reaction (MLR) in vitro. CFSE-labeled human mononuclear cells (MNCs) were cultured for five days in the presence of mitogen or antibodies for CD3/28 with or without Ech A treatment, then the percentage of proliferated cells was evaluated using flow cytometry. The proliferation of both MNCs (A,B) and T cells (C,D) was reduced by Ech A treatment in a dose-dependent manner. VC, vehicle-treated control. ** P < 0.01. Results are shown as mean ± SD.
Figure 3. Ech A impact on Th cell polarization in vitro. (A,B) the percentages of IFN-γ + and IL-4+ cells among CD4+ Th cells were evaluated using flow cytometry to determine the induction ratio of Th1 and Th2 cells, respectively. No significant change was observed upon Ech A treatment. (C) Spontaneous generation of Foxp3+ Treg cells among CD4+ Th cells upon vehicle and Ech A treatment was assessed using flow cytometry. Ech A treatment led to an increase in Treg population compared to the vehicle-treated group. VC, vehicle-treated control. * P < 0.05, ** P < 0.001. Results are shown as mean ± SD.
Figure 4. Ech A impact on M1/M2 macrophage polarization in vitro. (A) After five days of M1 induction, TNF-α concentration in the culture supernatant was measured by ELISA to estimate the M1 polarization efficiency. It is noted that Ech A prevented M1 polarization in vitro in a dose-dependent manner. (B) The IL-10 secretion level was determined using ELISA to evaluate the spontaneous M2 induction efficiency. Ech A treated macrophages were differentiated into M2 macrophages more effectively compared to vehicle-treated cells; (–), no induction control; (+), polarization induced control. The p-value significance was calculated by comparing other groups against the (+) and (–) groups (marked as +) in A and B, respectively. * P < 0.05, ** P < 0.01, *** P < 0.001. Results are shown as mean ± SD.
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