Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis

Wenwei Zhong, Zhenwei Xia, David Hinrichs, James (Jim) Rosenbaum, Keith W. Wegmann, Jeffery Meyrowitz, Zili Zhang

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Objective: Inflammatory bowel disease (IBD) is characterized by recurrent and severe gastrointestinal inflammation. Activation of inflammatory cells, such as T H17 lymphocytes, and/or deficiency of regulatory T cells (T reg) are responsible for the pathogenesis of IBD. As an acute phase reactant, heme oxygenase-1 (HO-1) has been shown to play an anti-inflammatory and immunomodulatory role in many disease processes. In this study, we used a dextran sulfate sodium (DSS)-induced murine colitis model to investigate the effect of upregulating HO-1 by hemin on the development of colonic inflammation. Materials and Methods: The mice were enterically challenged with 4% DSS. In addition, some mice were intraperitoneally administered with hemin or Sn-protoporphyrin (SnPP) on days 0, 1, and 6 after DSS treatment. The severity of colitis was evaluated by daily monitoring of weight change and diarrhea. At the end of the experiment, the colon, spleen, and mesenteric lymph nodes were harvested for histology and various immunological assays. Results: Compared to control groups, DSS challenge markedly induced HO-1 expression in the colon epithelium. Upregulation of HO-1 by hemin was further correlated with attenuation of DSS-induced colitis. In contrast, inhibition of endogenous HO-1 by SnPP aggravated the colitis. To further assess the anti-inflammatory mechanisms, we examined whether hemin enhanced the proliferation of Treg cells and suppressed the production of interleukin (IL)-17. Flow cytometry analysis revealed that hemin markedly expanded the CD4 + CD25 + Foxp3+ T reg population. Moreover, hemin attenuated IL-17 and TH17-related cytokines. This inhibition coincided with the attenuation of DSS-induced colitis. Finally, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling assay showed that hemin treatment markedly reduced programmed cell death of colonic epithelium, indicating that hemin exerts a modulatory effect on the induction of Treg, IL-17, and apoptosis. Conclusions: These results demonstrate that upregulation of HO-1 by hemin ameliorated experimental colitis. Moreover, our study suggests a broader protective mechanism of hemin.

Original languageEnglish (US)
Pages (from-to)132-139
Number of pages8
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume50
Issue number2
DOIs
StatePublished - Feb 2010

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Hemin
Dextran Sulfate
Colitis
Heme Oxygenase-1
Interleukin-17
Regulatory T-Lymphocytes
Inflammatory Bowel Diseases
Colon
Anti-Inflammatory Agents
Up-Regulation
Epithelium
Inflammation
DNA Nucleotidylexotransferase
Acute-Phase Proteins
Diarrhea
Histology
Flow Cytometry
Cell Death
Spleen
Lymph Nodes

Keywords

  • Colitis
  • Inflammatory bowel disease
  • Interleukin-17
  • Regulatory T cells

ASJC Scopus subject areas

  • Gastroenterology
  • Pediatrics, Perinatology, and Child Health

Cite this

Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis. / Zhong, Wenwei; Xia, Zhenwei; Hinrichs, David; Rosenbaum, James (Jim); Wegmann, Keith W.; Meyrowitz, Jeffery; Zhang, Zili.

In: Journal of Pediatric Gastroenterology and Nutrition, Vol. 50, No. 2, 02.2010, p. 132-139.

Research output: Contribution to journalArticle

Zhong, Wenwei ; Xia, Zhenwei ; Hinrichs, David ; Rosenbaum, James (Jim) ; Wegmann, Keith W. ; Meyrowitz, Jeffery ; Zhang, Zili. / Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis. In: Journal of Pediatric Gastroenterology and Nutrition. 2010 ; Vol. 50, No. 2. pp. 132-139.
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T1 - Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis

AU - Zhong, Wenwei

AU - Xia, Zhenwei

AU - Hinrichs, David

AU - Rosenbaum, James (Jim)

AU - Wegmann, Keith W.

AU - Meyrowitz, Jeffery

AU - Zhang, Zili

PY - 2010/2

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N2 - Objective: Inflammatory bowel disease (IBD) is characterized by recurrent and severe gastrointestinal inflammation. Activation of inflammatory cells, such as T H17 lymphocytes, and/or deficiency of regulatory T cells (T reg) are responsible for the pathogenesis of IBD. As an acute phase reactant, heme oxygenase-1 (HO-1) has been shown to play an anti-inflammatory and immunomodulatory role in many disease processes. In this study, we used a dextran sulfate sodium (DSS)-induced murine colitis model to investigate the effect of upregulating HO-1 by hemin on the development of colonic inflammation. Materials and Methods: The mice were enterically challenged with 4% DSS. In addition, some mice were intraperitoneally administered with hemin or Sn-protoporphyrin (SnPP) on days 0, 1, and 6 after DSS treatment. The severity of colitis was evaluated by daily monitoring of weight change and diarrhea. At the end of the experiment, the colon, spleen, and mesenteric lymph nodes were harvested for histology and various immunological assays. Results: Compared to control groups, DSS challenge markedly induced HO-1 expression in the colon epithelium. Upregulation of HO-1 by hemin was further correlated with attenuation of DSS-induced colitis. In contrast, inhibition of endogenous HO-1 by SnPP aggravated the colitis. To further assess the anti-inflammatory mechanisms, we examined whether hemin enhanced the proliferation of Treg cells and suppressed the production of interleukin (IL)-17. Flow cytometry analysis revealed that hemin markedly expanded the CD4 + CD25 + Foxp3+ T reg population. Moreover, hemin attenuated IL-17 and TH17-related cytokines. This inhibition coincided with the attenuation of DSS-induced colitis. Finally, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling assay showed that hemin treatment markedly reduced programmed cell death of colonic epithelium, indicating that hemin exerts a modulatory effect on the induction of Treg, IL-17, and apoptosis. Conclusions: These results demonstrate that upregulation of HO-1 by hemin ameliorated experimental colitis. Moreover, our study suggests a broader protective mechanism of hemin.

AB - Objective: Inflammatory bowel disease (IBD) is characterized by recurrent and severe gastrointestinal inflammation. Activation of inflammatory cells, such as T H17 lymphocytes, and/or deficiency of regulatory T cells (T reg) are responsible for the pathogenesis of IBD. As an acute phase reactant, heme oxygenase-1 (HO-1) has been shown to play an anti-inflammatory and immunomodulatory role in many disease processes. In this study, we used a dextran sulfate sodium (DSS)-induced murine colitis model to investigate the effect of upregulating HO-1 by hemin on the development of colonic inflammation. Materials and Methods: The mice were enterically challenged with 4% DSS. In addition, some mice were intraperitoneally administered with hemin or Sn-protoporphyrin (SnPP) on days 0, 1, and 6 after DSS treatment. The severity of colitis was evaluated by daily monitoring of weight change and diarrhea. At the end of the experiment, the colon, spleen, and mesenteric lymph nodes were harvested for histology and various immunological assays. Results: Compared to control groups, DSS challenge markedly induced HO-1 expression in the colon epithelium. Upregulation of HO-1 by hemin was further correlated with attenuation of DSS-induced colitis. In contrast, inhibition of endogenous HO-1 by SnPP aggravated the colitis. To further assess the anti-inflammatory mechanisms, we examined whether hemin enhanced the proliferation of Treg cells and suppressed the production of interleukin (IL)-17. Flow cytometry analysis revealed that hemin markedly expanded the CD4 + CD25 + Foxp3+ T reg population. Moreover, hemin attenuated IL-17 and TH17-related cytokines. This inhibition coincided with the attenuation of DSS-induced colitis. Finally, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling assay showed that hemin treatment markedly reduced programmed cell death of colonic epithelium, indicating that hemin exerts a modulatory effect on the induction of Treg, IL-17, and apoptosis. Conclusions: These results demonstrate that upregulation of HO-1 by hemin ameliorated experimental colitis. Moreover, our study suggests a broader protective mechanism of hemin.

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