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IL-6 stimulates intestinal epithelial proliferation and repair after injury.

Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS - PLoS ONE (2014)

Bottom Line: IL-6 is a pleiotropic cytokine often associated with inflammation.Inhibition of this pathway has led to successful treatment of rheumatoid arthritis, but one unforeseen potential complication of anti-IL-6 therapy is bowel perforation.Inhibition of IL-6 resulted in impaired wound healing due to decreased epithelial proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.

ABSTRACT
IL-6 is a pleiotropic cytokine often associated with inflammation. Inhibition of this pathway has led to successful treatment of rheumatoid arthritis, but one unforeseen potential complication of anti-IL-6 therapy is bowel perforation. Within the intestine, IL-6 has been shown to prevent epithelial apoptosis during prolonged inflammation. The role of IL-6 in the intestine during an initial inflammatory insult is unknown. Here, we evaluate the role of IL-6 at the onset of an inflammatory injury. Using two murine models of bowel injury - wound by biopsy and bacterial triggered colitis - we demonstrated that IL-6 is induced soon after injury by multiple cell types including intraepithelial lymphocytes. Inhibition of IL-6 resulted in impaired wound healing due to decreased epithelial proliferation. Using intestinal tissue obtained from patients who underwent surgical resection of the colon due to traumatic perforation, we observed cells with detectable IL-6 within the area of perforation and not at distant sites. Our data demonstrate the important role of IL-6 produced in part by intraepithelial lymphocytes at the onset of an inflammatory injury for epithelial proliferation and wound repair.

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IL-6 was induced with the initiation of colitis in dnKO mice.Antibiotic pretreated dnKO and IL-10rb+/- littermate control mice were co-housed with non-antibiotic treated mice to induce colitis in dnKO mice. From individual mice, colons and sera were harvested with no co-housing (baseline, day zero) and every three days after co-housing. IL-6 mRNA and protein expression was analyzed by ELISA (A) and in situ hybridization (B), respectively. Two experiments were performed with a total of 10–14 mice/group/time point. (A) Plot of the average ± SEM IL-6 protein (pg/ml) in the sera over time for each group of mice. A student's t-test was used to determine statistical significance for each time point; *, p<0.05; **, p<0.0001. (B) Representative images of IL-6 in situ hybridization (red staining, arrowheads) are shown for days 0, 3 and 6 post co-housing. Bars = 500 µm.
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pone-0114195-g001: IL-6 was induced with the initiation of colitis in dnKO mice.Antibiotic pretreated dnKO and IL-10rb+/- littermate control mice were co-housed with non-antibiotic treated mice to induce colitis in dnKO mice. From individual mice, colons and sera were harvested with no co-housing (baseline, day zero) and every three days after co-housing. IL-6 mRNA and protein expression was analyzed by ELISA (A) and in situ hybridization (B), respectively. Two experiments were performed with a total of 10–14 mice/group/time point. (A) Plot of the average ± SEM IL-6 protein (pg/ml) in the sera over time for each group of mice. A student's t-test was used to determine statistical significance for each time point; *, p<0.05; **, p<0.0001. (B) Representative images of IL-6 in situ hybridization (red staining, arrowheads) are shown for days 0, 3 and 6 post co-housing. Bars = 500 µm.

Mentions: We first determined the timing of IL-6 expression with respect to the induction of intestinal inflammation. We used dnKO mice (transgenic for a dominant negative Tgfbr2 expressed in T cells and a knockout of the IL10rb gene) as this is an established model of triggered colonic inflammation [17]. We have previously shown that after a three week period of antibiotic treatment beginning at weaning, pan-colitis is induced by the introduction of colitigenic bacteria [18]. In this study, we triggered colitis by co-housing antibiotic pre-treated dnKO mice with untreated IL10rb+/− littermates. We first determined IL-6 expression by serum ELISA from samples taken at three day intervals after the initiation of co-housing. We found that day six post co-housing was the first time point where IL-6 was significantly increased in dnKO mice as compared to similar treated IL10rb+/− littermate controls (Figure 1A). This time point was of interest as it corresponded to the maximal colonization of colitigentic microbes and the induction of colitis [18]. We confirmed the timing of IL-6 induction by in situ hybridization of colonic sections taken at days zero, three and six post co-housing. This analysis also showed that IL-6 was first detected at day six post co-housing (Figure 1B). Interestingly, many of the IL-6 positive cells were closely associated with intestinal crypts.


IL-6 stimulates intestinal epithelial proliferation and repair after injury.

Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS - PLoS ONE (2014)

IL-6 was induced with the initiation of colitis in dnKO mice.Antibiotic pretreated dnKO and IL-10rb+/- littermate control mice were co-housed with non-antibiotic treated mice to induce colitis in dnKO mice. From individual mice, colons and sera were harvested with no co-housing (baseline, day zero) and every three days after co-housing. IL-6 mRNA and protein expression was analyzed by ELISA (A) and in situ hybridization (B), respectively. Two experiments were performed with a total of 10–14 mice/group/time point. (A) Plot of the average ± SEM IL-6 protein (pg/ml) in the sera over time for each group of mice. A student's t-test was used to determine statistical significance for each time point; *, p<0.05; **, p<0.0001. (B) Representative images of IL-6 in situ hybridization (red staining, arrowheads) are shown for days 0, 3 and 6 post co-housing. Bars = 500 µm.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4257684&req=5

pone-0114195-g001: IL-6 was induced with the initiation of colitis in dnKO mice.Antibiotic pretreated dnKO and IL-10rb+/- littermate control mice were co-housed with non-antibiotic treated mice to induce colitis in dnKO mice. From individual mice, colons and sera were harvested with no co-housing (baseline, day zero) and every three days after co-housing. IL-6 mRNA and protein expression was analyzed by ELISA (A) and in situ hybridization (B), respectively. Two experiments were performed with a total of 10–14 mice/group/time point. (A) Plot of the average ± SEM IL-6 protein (pg/ml) in the sera over time for each group of mice. A student's t-test was used to determine statistical significance for each time point; *, p<0.05; **, p<0.0001. (B) Representative images of IL-6 in situ hybridization (red staining, arrowheads) are shown for days 0, 3 and 6 post co-housing. Bars = 500 µm.
Mentions: We first determined the timing of IL-6 expression with respect to the induction of intestinal inflammation. We used dnKO mice (transgenic for a dominant negative Tgfbr2 expressed in T cells and a knockout of the IL10rb gene) as this is an established model of triggered colonic inflammation [17]. We have previously shown that after a three week period of antibiotic treatment beginning at weaning, pan-colitis is induced by the introduction of colitigenic bacteria [18]. In this study, we triggered colitis by co-housing antibiotic pre-treated dnKO mice with untreated IL10rb+/− littermates. We first determined IL-6 expression by serum ELISA from samples taken at three day intervals after the initiation of co-housing. We found that day six post co-housing was the first time point where IL-6 was significantly increased in dnKO mice as compared to similar treated IL10rb+/− littermate controls (Figure 1A). This time point was of interest as it corresponded to the maximal colonization of colitigentic microbes and the induction of colitis [18]. We confirmed the timing of IL-6 induction by in situ hybridization of colonic sections taken at days zero, three and six post co-housing. This analysis also showed that IL-6 was first detected at day six post co-housing (Figure 1B). Interestingly, many of the IL-6 positive cells were closely associated with intestinal crypts.

Bottom Line: IL-6 is a pleiotropic cytokine often associated with inflammation.Inhibition of this pathway has led to successful treatment of rheumatoid arthritis, but one unforeseen potential complication of anti-IL-6 therapy is bowel perforation.Inhibition of IL-6 resulted in impaired wound healing due to decreased epithelial proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.

ABSTRACT
IL-6 is a pleiotropic cytokine often associated with inflammation. Inhibition of this pathway has led to successful treatment of rheumatoid arthritis, but one unforeseen potential complication of anti-IL-6 therapy is bowel perforation. Within the intestine, IL-6 has been shown to prevent epithelial apoptosis during prolonged inflammation. The role of IL-6 in the intestine during an initial inflammatory insult is unknown. Here, we evaluate the role of IL-6 at the onset of an inflammatory injury. Using two murine models of bowel injury - wound by biopsy and bacterial triggered colitis - we demonstrated that IL-6 is induced soon after injury by multiple cell types including intraepithelial lymphocytes. Inhibition of IL-6 resulted in impaired wound healing due to decreased epithelial proliferation. Using intestinal tissue obtained from patients who underwent surgical resection of the colon due to traumatic perforation, we observed cells with detectable IL-6 within the area of perforation and not at distant sites. Our data demonstrate the important role of IL-6 produced in part by intraepithelial lymphocytes at the onset of an inflammatory injury for epithelial proliferation and wound repair.

Show MeSH
Related in: MedlinePlus