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Interleukin 13 and serotonin: linking the immune and endocrine systems in murine models of intestinal inflammation.

Shajib MS, Wang H, Kim JJ, Sunjic I, Ghia JE, Denou E, Collins M, Denburg JA, Khan WI - PLoS ONE (2013)

Bottom Line: Following DSS administration, significantly lower pro-inflammatory cytokine production and fewer infiltrating macrophages were observed in IL-13-/- mice compared to WT.These results demonstrate that IL-13 plays a critical role in the pathogenesis of experimental colitis and 5-HT is an important mediator of IL-13 driven intestinal inflammation.This study revealed important information on immune-endocrine axis in gut in relation to inflammation which may ultimately lead to better strategy in managing various intestinal inflammatory conditions including inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada ; Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

ABSTRACT

Objective: Infiltration of activated immune cells and increased cytokine production define the immunophenotype of gastrointestinal (GI) inflammation. In addition, intestinal inflammation is accompanied by alteration in the numbers of serotonin (5-hydroxytryptamine; 5-HT) synthesizing enterochromaffin (EC) cells and in 5-HT amount. It has been established that EC cells express interleukin (IL)-13 receptor, additionally IL-13 has been implicated in the pathogenesis of ulcerative colitis. In this study, we investigated the role of IL-13 mediated 5-HT signaling in pathogenesis of colitis.

Methodology: Colitis was induced in IL-13 deficient (IL-13-/-) and wild-type (WT) mice with dextran sulfate sodium (DSS) and dinitrobenzene sulfonic acid (DNBS), as well as in IL-13-/- mice given recombinant mouse IL-13 (rmIL-13) and 5-hydroxytryptamine (5-HTP), the direct precursor of 5-HT.

Principal findings and conclusion: Elevated colonic IL-13 levels were observed in WT mice receiving DSS in comparison to control. IL-13-/- mice administered DSS exhibited significantly reduced severity of colitis compared to WT mice as reflected by macroscopic and histological damage assessments. Following DSS administration, significantly lower pro-inflammatory cytokine production and fewer infiltrating macrophages were observed in IL-13-/- mice compared to WT. The reduced severity of colitis observed in IL-13-/- mice was also accompanied by down-regulation of EC cell numbers and colonic 5-HT content. In addition, increasing colonic 5-HT content by administration of rmIL-13 or 5-HTP exacerbated severity of DSS colitis in IL-13-/- mice. IL-13-/- mice also exhibited reduced severity of DNBS-induced colitis. These results demonstrate that IL-13 plays a critical role in the pathogenesis of experimental colitis and 5-HT is an important mediator of IL-13 driven intestinal inflammation. This study revealed important information on immune-endocrine axis in gut in relation to inflammation which may ultimately lead to better strategy in managing various intestinal inflammatory conditions including inflammatory bowel disease.

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Effects of 5-HTP administration in IL-13−/− mice in DSS-induced colitis.5-HTP 100 mg/kg treatment started 3 days prior to 5 days of 5% DSS administration, control groups received saline. (A) Colonic 5-HT levels (B) DAI (C) Macroscopic scores (D) Histological scores (i) and (ii) Representative light micrograph of an H&E-stained colonic section. From colonic tissue (E) IL-1β and (F) IL-6 levels. DAI data represented as mean ± SEM from 4 to 6 mice; *represents statistical significance where p<0.05; #significant difference between IL-13−/− +5-HTP and IL-13−/− +saline, both groups receiving DSS; @ indicates no significant difference between IL-13−/− groups receiving saline as vehicle.
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pone-0072774-g005: Effects of 5-HTP administration in IL-13−/− mice in DSS-induced colitis.5-HTP 100 mg/kg treatment started 3 days prior to 5 days of 5% DSS administration, control groups received saline. (A) Colonic 5-HT levels (B) DAI (C) Macroscopic scores (D) Histological scores (i) and (ii) Representative light micrograph of an H&E-stained colonic section. From colonic tissue (E) IL-1β and (F) IL-6 levels. DAI data represented as mean ± SEM from 4 to 6 mice; *represents statistical significance where p<0.05; #significant difference between IL-13−/− +5-HTP and IL-13−/− +saline, both groups receiving DSS; @ indicates no significant difference between IL-13−/− groups receiving saline as vehicle.

Mentions: To evaluate the role of decreased 5-HT production in IL-13−/− mice and its significance in the reduced severity of DSS-colitis in these animals, we treated IL-13−/− mice with 5-HTP, the direct precursor of 5-HT. A significant increase in colonic 5-HT content was observed in IL-13−/− mice receiving 5-HTP compared to IL-13−/− receiving vehicle following induction of DSS colitis (Figure 5A). IL-13−/− mice treated with 5-HTP had significantly higher disease activity scores compared to the vehicle treated group (Figure 5B). Post-mortem macroscopic assessment and histopathological evaluation also revealed significant enhancement of severity of colitis in IL-13−/− mice that received 5-HTP as compared to the IL-13−/− mice that received vehicle (Figure 5C and D). This increase in severity of colitis observed in 5-HTP treated groups was also resulted in increased levels of colonic IL-1β and IL-6 (Figure 5E and F).


Interleukin 13 and serotonin: linking the immune and endocrine systems in murine models of intestinal inflammation.

Shajib MS, Wang H, Kim JJ, Sunjic I, Ghia JE, Denou E, Collins M, Denburg JA, Khan WI - PLoS ONE (2013)

Effects of 5-HTP administration in IL-13−/− mice in DSS-induced colitis.5-HTP 100 mg/kg treatment started 3 days prior to 5 days of 5% DSS administration, control groups received saline. (A) Colonic 5-HT levels (B) DAI (C) Macroscopic scores (D) Histological scores (i) and (ii) Representative light micrograph of an H&E-stained colonic section. From colonic tissue (E) IL-1β and (F) IL-6 levels. DAI data represented as mean ± SEM from 4 to 6 mice; *represents statistical significance where p<0.05; #significant difference between IL-13−/− +5-HTP and IL-13−/− +saline, both groups receiving DSS; @ indicates no significant difference between IL-13−/− groups receiving saline as vehicle.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755966&req=5

pone-0072774-g005: Effects of 5-HTP administration in IL-13−/− mice in DSS-induced colitis.5-HTP 100 mg/kg treatment started 3 days prior to 5 days of 5% DSS administration, control groups received saline. (A) Colonic 5-HT levels (B) DAI (C) Macroscopic scores (D) Histological scores (i) and (ii) Representative light micrograph of an H&E-stained colonic section. From colonic tissue (E) IL-1β and (F) IL-6 levels. DAI data represented as mean ± SEM from 4 to 6 mice; *represents statistical significance where p<0.05; #significant difference between IL-13−/− +5-HTP and IL-13−/− +saline, both groups receiving DSS; @ indicates no significant difference between IL-13−/− groups receiving saline as vehicle.
Mentions: To evaluate the role of decreased 5-HT production in IL-13−/− mice and its significance in the reduced severity of DSS-colitis in these animals, we treated IL-13−/− mice with 5-HTP, the direct precursor of 5-HT. A significant increase in colonic 5-HT content was observed in IL-13−/− mice receiving 5-HTP compared to IL-13−/− receiving vehicle following induction of DSS colitis (Figure 5A). IL-13−/− mice treated with 5-HTP had significantly higher disease activity scores compared to the vehicle treated group (Figure 5B). Post-mortem macroscopic assessment and histopathological evaluation also revealed significant enhancement of severity of colitis in IL-13−/− mice that received 5-HTP as compared to the IL-13−/− mice that received vehicle (Figure 5C and D). This increase in severity of colitis observed in 5-HTP treated groups was also resulted in increased levels of colonic IL-1β and IL-6 (Figure 5E and F).

Bottom Line: Following DSS administration, significantly lower pro-inflammatory cytokine production and fewer infiltrating macrophages were observed in IL-13-/- mice compared to WT.These results demonstrate that IL-13 plays a critical role in the pathogenesis of experimental colitis and 5-HT is an important mediator of IL-13 driven intestinal inflammation.This study revealed important information on immune-endocrine axis in gut in relation to inflammation which may ultimately lead to better strategy in managing various intestinal inflammatory conditions including inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada ; Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

ABSTRACT

Objective: Infiltration of activated immune cells and increased cytokine production define the immunophenotype of gastrointestinal (GI) inflammation. In addition, intestinal inflammation is accompanied by alteration in the numbers of serotonin (5-hydroxytryptamine; 5-HT) synthesizing enterochromaffin (EC) cells and in 5-HT amount. It has been established that EC cells express interleukin (IL)-13 receptor, additionally IL-13 has been implicated in the pathogenesis of ulcerative colitis. In this study, we investigated the role of IL-13 mediated 5-HT signaling in pathogenesis of colitis.

Methodology: Colitis was induced in IL-13 deficient (IL-13-/-) and wild-type (WT) mice with dextran sulfate sodium (DSS) and dinitrobenzene sulfonic acid (DNBS), as well as in IL-13-/- mice given recombinant mouse IL-13 (rmIL-13) and 5-hydroxytryptamine (5-HTP), the direct precursor of 5-HT.

Principal findings and conclusion: Elevated colonic IL-13 levels were observed in WT mice receiving DSS in comparison to control. IL-13-/- mice administered DSS exhibited significantly reduced severity of colitis compared to WT mice as reflected by macroscopic and histological damage assessments. Following DSS administration, significantly lower pro-inflammatory cytokine production and fewer infiltrating macrophages were observed in IL-13-/- mice compared to WT. The reduced severity of colitis observed in IL-13-/- mice was also accompanied by down-regulation of EC cell numbers and colonic 5-HT content. In addition, increasing colonic 5-HT content by administration of rmIL-13 or 5-HTP exacerbated severity of DSS colitis in IL-13-/- mice. IL-13-/- mice also exhibited reduced severity of DNBS-induced colitis. These results demonstrate that IL-13 plays a critical role in the pathogenesis of experimental colitis and 5-HT is an important mediator of IL-13 driven intestinal inflammation. This study revealed important information on immune-endocrine axis in gut in relation to inflammation which may ultimately lead to better strategy in managing various intestinal inflammatory conditions including inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus