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. 2021 Dec 21;27(47):8138-8155.
doi: 10.3748/wjg.v27.i47.8138.

Impact of intrarectal chromofungin treatment on dendritic cells-related markers in different immune compartments in colonic inflammatory conditions

Kunal Kapoor  1 , Nour Eissa  1 , Diane Tshikudi  1 , Charles N Bernstein  2 , Jean-Eric Ghia  1
Affiliations

Impact of intrarectal chromofungin treatment on dendritic cells-related markers in different immune compartments in colonic inflammatory conditions

Kunal Kapoor et al. World J Gastroenterol. .

Abstract

Background: Chromofungin (CHR: chromogranin-A 47-66) is a chromogranin-A derived peptide with anti-inflammatory and anti-microbial properties. Ulcerative colitis (UC) is characterized by a colonic decrease of CHR and a dysregulation of dendritic CD11c+ cells.

Aim: To investigate the association between CHR treatment and dendritic cells (DCs)-related markers in different immune compartments in colitis.

Methods: A model of acute UC-like colitis using dextran sulphate sodium (DSS) was used in addition to biopsies collected from UC patients.

Results: Intrarectal CHR treatment reduced the severity of DSS-induced colitis and was associated with a significant decrease in the expression of CD11c, CD40, CD80, CD86 and interleukin (IL)-12p40 in the inflamed colonic mucosa and CD11c, CD80, CD86 IL-6 and IL-12p40 within the mesenteric lymph nodes and the spleen. Furthermore, CHR treatment decreased CD80 and CD86 expression markers of splenic CD11c+ cells and decreased NF-κB expression in the colon and of splenic CD11c+ cells. In vitro, CHR decreased CD40, CD80, CD86 IL-6 and IL-12p40 expression in naïve bone marrow-derived CD11c+ DCs stimulated with lipopolysaccharide. Pharmacological studies demonstrated an impact of CHR on the NF-κB pathway. In patients with active UC, CHR level was reduced and showed a negative linear relationship with CD11c and CD86.

Conclusion: CHR has protective properties against intestinal inflammation via the regulation of DC-related markers and CD11c+ cells. CHR could be a potential therapy of UC.

Keywords: Chromofungin; Chromogranin-A; Colitis; Cytokines; Dendritic cells; Gut hormones.

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Conflict of interest statement

Conflict-of-interest statement: Bernstein CN has been on the advisory boards for Abbvie Canada, Amgen Canada, Bristol Myers Squibb Canada, Janssen Canada, Roche Canada, Sandoz Canada, Takeda Canada, Pfizer Canada and consulted to Takeda and Mylan Pharmaceuticals. He has received educational grants from Abbvie Canada, Pfizer Canada, Takeda Canada, Janssen Canada. He has been on speaker’s panel for Abbvie Canada, Medtronic Canada and Janssen Canada. The other authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Chromofungin (chromogranin-A 47-66) treatment decreases dextran sulphate sodium-induced experimental colitis and colonic colonic cluster of differentiation markers and NF-κB gene expression in dextran sulphate sodium-induced experimental colitis. Colitis was induced with 5% dextran sulphate sodium in drinking water to C57BL/6 male mice, and the control group of mice received regular drinking water. Chromofungin (2.5 mg/kg per day, i.r.) was given as a preventive treatment or phosphate buffer saline (1%) starting from one day before the induction of colitis till the fifth day when the mice were sacrificed. A-C: External disease activity index recorded over the period of 5 d (A), macroscopic scores at sacrifice day (B), CD86 and 80 and NF-κB gene expression profile by RT2 profiler PCR array at sacrifice day (C). Unpaired two-tailed Mann-Whitney U and Two-way repeated measures or One-way ANOVA followed by multiple comparison tests were used to analyze the data, and adjusted P equal to or smaller than 0.05 is believed to be significant. Each value represents the mean ± SE, n = 6 mice/group. PBS: Phosphate buffer saline; CHR: Chromofungin; DSS: Dextran sulphate sodium.
Figure 2
Figure 2
Chromofungin (chromogranin-A 47-66) treatment decreases colonic cluster of differentiation markers and interleukin-12 level in dextran sulphate sodium-induced experimental colitis. Colitis was induced with 5% dextran sulphate sodium in drinking water to C57BL/6 male mice, and the control group of mice received regular drinking water. Chromofungin (2.5 mg/kg per day, i.r.) was given as a preventive treatment or phosphate buffer saline (1%) starting from one day before the induction of colitis till the fifth day when the mice were sacrificed. A-F: CD86 (A), CD80 (B), CD40 (C), CD11c (D), interleukin (IL)-12p40 mRNA expression (E), IL-12p40 protein level (F). mRNA expression was quantified by quantitative real-time reverse-transcription polymerase chain reaction and protein level by ELISA. One-way ANOVA followed by multiple comparison tests was used to analyze the data, and adjusted P equal to or smaller than 0.05 is believed to be significant. Each value represents the mean ± SE, n = 6 mice/group. PBS: Phosphate buffer saline; CHR: Chromofungin; DSS: Dextran sulphate sodium.
Figure 3
Figure 3
Chromofungin (chromogranin-A 47-66) treatment decreases mesenteric lymph node cluster of differentiation markers and cytokine levels in dextran sulphate sodium-induced experimental colitis. Colitis was induced with 5% dextran sulphate sodium in drinking water to C57BL/6 male mice, and the control group of mice received regular drinking water. Chromofungin (2.5 mg/kg per day, i.r.) was given as a preventive treatment or phosphate buffer saline (1%) starting from one day before the induction of colitis till the fifth day when the mice were sacrificed. A-E: CD86 (A), CD80 (B), CD11c (C), interleukin (IL)-12p40 (D), IL-6 mRNA expression (E). mRNA expression was quantified by quantitative real-time reverse-transcription polymerase chain reaction. One-way ANOVA followed by multiple comparison tests was used to analyze the data, and adjusted P equal to or smaller than 0.05 is believed to be significant. Each value represents the mean ± SE, n = 6 mice/group. PBS: Phosphate buffer saline; CHR: Chromofungin; DSS: Dextran sulphate sodium.
Figure 4
Figure 4
Chromofungin (chromogranin-A 47-66) treatment decreases splenocyte cluster of differentiation markers and interleukin-12 level in dextran sulphate sodium-induced experimental colitis. Colitis was induced with 5% dextran sulphate sodium in drinking water to C57BL/6 male mice, and the control group of mice received regular drinking water. Chromofungin (2.5 mg/kg per day, i.r.) was given as a preventive treatment or phosphate buffer saline (1%) starting from one day before the induction of colitis till the fifth day when the mice were sacrificed. A-E: CD86 (A), CD80 (B), CD11c (C), interleukin (IL)-12p40 (D), IL-6 mRNA expression (E) from splenic cells. mRNA expression was quantified by quantitative real-time reverse-transcription polymerase chain reaction. One-way ANOVA followed by multiple comparison tests was used to analyze the data, and adjusted P equal to or smaller than 0.05 is believed to be significant. Each value represents the mean ± SE, n = 6 mice/group. PBS: Phosphate buffer saline; CHR: Chromofungin; DSS: Dextran sulphate sodium.
Figure 5
Figure 5
Chromofungin (chromogranin-A 47-66) treatment decreases dextran sulphate sodium-induced experimental colitis and colonic cluster of differentiation markers and NF-κB gene expression in dextran sulphate sodium-induced experimental colitis. CD86 and 80 and NF-κB gene expression profile by RT2 profiler polymerase chain reaction array at sacrifice day. One-way ANOVA followed by multiple comparison tests were used to analyze the data, and adjusted P equal to or smaller than 0.05 is believed to be significant. Each value represents the mean ± SE, n = 6 mice/group.
Figure 6
Figure 6
Chromofungin (chromogranin-A 47-66) treatment decreases lipopolysaccharide-stimulated bone marrow-derived CD11c+ cells' cluster of differentiation markers and cytokine-associated level via the NF-κB pathways. Bone marrow-derived CD11c+ cells using MACS technique were isolated and cultured with granulocyte-macrophage induced colony-stimulating factor for 8 d until full maturation. Cells were treated with CHR (10-6 M/mL) for 12 h and then stimulated with lipopolysaccharide (100 ng/mL) in the presence or absence of NF-κB activator/stimulator (10 u/mL) for 24 h. A-E: CD86 (A), CD80 (B), CD40 (C), mRNA expression and IL-12p40 (D), IL-6 (E) medium protein level. mRNA expression was quantified by quantitative real-time reverse-transcription polymerase chain reaction and protein levels were quantified by ELISA. One-way ANOVA followed by multiple comparison tests was used to analyze the data, and adjusted P equal to or smaller than 0.05 is believed to be significant. Each value represents the mean ± SE, n = 6 mice/group. LPS: Lipopolysaccharide; CHR: Chromofungin.
Figure 7
Figure 7
Chromofungin (CHGA Exon-IV) correlates negatively with cluster of differentiation 86 and 80 mRNA expression. A: mRNA expression of CD86 in the colonic tissue of healthy individuals (n = 10) and participants with active ulcerative colitis (UC) (n = 10); B: Correlation analysis between biopsy CHGA Exon IV and CD86 mRNA expression; C: mRNA expression of CD80 in the colonic tissue of healthy individuals (n = 10) and participants with active UC (n = 10); D: Correlation analysis between biopsy CHGA Exon IV and CD80 mRNA expression. mRNA expression was quantified by quantitative real-time reverse-transcription polymerase chain reaction. Student t-test and Mann-Whitney test and Spearman's correlation were used to analyze, and adjusted P equal to or smaller than 0.05 is believed to be significant. UC: Ulcerative colitis.
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