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Overexpression of CIITA in T cells aggravates Th2-mediated colitis in mice.

Kim TW, Park HJ, Choi EY, Jung KC - J. Korean Med. Sci. (2006)

Bottom Line: The MHC class II transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC class II restricted antigen presentation.Previously we suggested another role of CIITA in Th1/Th2 balance by demonstrating that forced expression of CIITA in murine T cells repressed Th1 immunity both in vitro and in vivo.And, CD4+ T cells from the mesenteric lymph node of CIITA-transgenic mice treated with oxazolone exhibited a high level of IL-4 secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Hallym University College of Medicine, Chuncheon, Korea.

ABSTRACT
The MHC class II transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC class II restricted antigen presentation. Previously we suggested another role of CIITA in Th1/Th2 balance by demonstrating that forced expression of CIITA in murine T cells repressed Th1 immunity both in vitro and in vivo. However, the results were contradictory to the report that CIITA functioned to suppress the production of Th2 cytokine by CD4+ T cells in CIITA deficient mice. In this study, we investigated the influence of constitutive expression of CIITA in T cells on Th2 immune response in vivo using murine experimental colitis model. In the dextran sodium sulfate-induced acute colitis, a disease involving innate immunity, CIITA transgenic mice and wild type control mice showed similar progression of the disease. However, the development of oxazolone-induced colitis, a colitis mediated by predominantly Th2 immune response, was aggravated in CIITA-transgenic mice. And, CD4+ T cells from the mesenteric lymph node of CIITA-transgenic mice treated with oxazolone exhibited a high level of IL-4 secretion. Together, these data demonstrate that constitutive expression of CIITA in T cells skews immune response to Th2, resulting in aggravation of Th2-mediated colitis in vivo.

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Gross and microscopic features of intestines showing aggravated inflammation in CIITA-transgenic (Tg) mice compared with wild type (WT) mice in response to oxazolone. (A) Treatment with oxazolone induced significant shortening of the colon, which was more significant in CIITA-transgenic mice. (B) Histology of colonic samples taken from mice receiving oxazolone. Colon from oxazolone-treated CIITA-transgenic mice on day 3 after the challenge of oxazolone per rectum shows more severe inflammation characterized by epithelial ulceration, destruction of glands and inflammatory cell infiltration in whole layer of bowel wall (right). While in oxazolone treated wild type mice (left), the colon shows restricted inflammatory cell infiltration to mucosa. (H&E stain, ×100).
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Figure 4: Gross and microscopic features of intestines showing aggravated inflammation in CIITA-transgenic (Tg) mice compared with wild type (WT) mice in response to oxazolone. (A) Treatment with oxazolone induced significant shortening of the colon, which was more significant in CIITA-transgenic mice. (B) Histology of colonic samples taken from mice receiving oxazolone. Colon from oxazolone-treated CIITA-transgenic mice on day 3 after the challenge of oxazolone per rectum shows more severe inflammation characterized by epithelial ulceration, destruction of glands and inflammatory cell infiltration in whole layer of bowel wall (right). While in oxazolone treated wild type mice (left), the colon shows restricted inflammatory cell infiltration to mucosa. (H&E stain, ×100).

Mentions: Next, we tested whether the over-expression of CIITA in peripheral T cells might influence Th2 immune response in vivo. Administration of oxazolone per rectum in the presence of ethanol induces a mucosal immune response leading to a rapidly developing colitis confined to the distal half of the colon in susceptible (SJL and C57BL/6) mouse strains (15). In this model, the inflammation is characterized by increased IL-4 and IL-5 secretion and the inflammation can be ameliorated by the administration of anti-IL-4 antibodies (15). CIITA-Tg mice and wild type littermates were sensitized by the epicutaneous application of 3% oxazolone solution onto the shaved abdomens, followed by administration of 1% oxazolone per rectum 5 days later. While control animals, which received 50% ethanol in PBS, appeared to have only a transient weight loss without morbidity, oxazolone-challenged B6 mice developed colitis, showing more severe weight loss that peaked 1 day after induction and sometimes culminated in death by day 3 (Fig. 3). This was accompanied by shortening of colonic length; 49±4 mm and 62±4 mm in oxazolone- and vehicle-treated mice, respectively. Microscopic examination of colon extracted from these mice on day 3 after oxazolone challenge per rectum showed histological evidence of severe colitis, which involved only the distal half of the bowel. Oxazolone-treated mice developed dense infiltration of the mucosa with small polynuclear granulocytes and lymphocytes (Fig. 4B). These clinical and pathologic features of oxazolone-induced colitis were significantly aggravated in CIITA-Tg mice. Treatment with oxazolone per rectum led to more severe weight loss and slow recovery in weight loss (Fig. 3A) in the CIITA-Tg mice, although survival rate was not statistically different from that of wild type littermate (p=0.37) (Fig. 3B). Macroscopically, the length of the colon in the oxazolone-treated CIITA Tg group (37±3 mm) was shorter than that in the wild type group treated with oxazolone (49±4 mm) (Fig. 4A). Histological findings showed significantly higher number of inflammatory cells infiltrating from mucosa to serosa of the colons in oxazolone-treated CIITA-Tg mice, compared with wild type controls (Fig. 4B).


Overexpression of CIITA in T cells aggravates Th2-mediated colitis in mice.

Kim TW, Park HJ, Choi EY, Jung KC - J. Korean Med. Sci. (2006)

Gross and microscopic features of intestines showing aggravated inflammation in CIITA-transgenic (Tg) mice compared with wild type (WT) mice in response to oxazolone. (A) Treatment with oxazolone induced significant shortening of the colon, which was more significant in CIITA-transgenic mice. (B) Histology of colonic samples taken from mice receiving oxazolone. Colon from oxazolone-treated CIITA-transgenic mice on day 3 after the challenge of oxazolone per rectum shows more severe inflammation characterized by epithelial ulceration, destruction of glands and inflammatory cell infiltration in whole layer of bowel wall (right). While in oxazolone treated wild type mice (left), the colon shows restricted inflammatory cell infiltration to mucosa. (H&E stain, ×100).
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Related In: Results  -  Collection

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Figure 4: Gross and microscopic features of intestines showing aggravated inflammation in CIITA-transgenic (Tg) mice compared with wild type (WT) mice in response to oxazolone. (A) Treatment with oxazolone induced significant shortening of the colon, which was more significant in CIITA-transgenic mice. (B) Histology of colonic samples taken from mice receiving oxazolone. Colon from oxazolone-treated CIITA-transgenic mice on day 3 after the challenge of oxazolone per rectum shows more severe inflammation characterized by epithelial ulceration, destruction of glands and inflammatory cell infiltration in whole layer of bowel wall (right). While in oxazolone treated wild type mice (left), the colon shows restricted inflammatory cell infiltration to mucosa. (H&E stain, ×100).
Mentions: Next, we tested whether the over-expression of CIITA in peripheral T cells might influence Th2 immune response in vivo. Administration of oxazolone per rectum in the presence of ethanol induces a mucosal immune response leading to a rapidly developing colitis confined to the distal half of the colon in susceptible (SJL and C57BL/6) mouse strains (15). In this model, the inflammation is characterized by increased IL-4 and IL-5 secretion and the inflammation can be ameliorated by the administration of anti-IL-4 antibodies (15). CIITA-Tg mice and wild type littermates were sensitized by the epicutaneous application of 3% oxazolone solution onto the shaved abdomens, followed by administration of 1% oxazolone per rectum 5 days later. While control animals, which received 50% ethanol in PBS, appeared to have only a transient weight loss without morbidity, oxazolone-challenged B6 mice developed colitis, showing more severe weight loss that peaked 1 day after induction and sometimes culminated in death by day 3 (Fig. 3). This was accompanied by shortening of colonic length; 49±4 mm and 62±4 mm in oxazolone- and vehicle-treated mice, respectively. Microscopic examination of colon extracted from these mice on day 3 after oxazolone challenge per rectum showed histological evidence of severe colitis, which involved only the distal half of the bowel. Oxazolone-treated mice developed dense infiltration of the mucosa with small polynuclear granulocytes and lymphocytes (Fig. 4B). These clinical and pathologic features of oxazolone-induced colitis were significantly aggravated in CIITA-Tg mice. Treatment with oxazolone per rectum led to more severe weight loss and slow recovery in weight loss (Fig. 3A) in the CIITA-Tg mice, although survival rate was not statistically different from that of wild type littermate (p=0.37) (Fig. 3B). Macroscopically, the length of the colon in the oxazolone-treated CIITA Tg group (37±3 mm) was shorter than that in the wild type group treated with oxazolone (49±4 mm) (Fig. 4A). Histological findings showed significantly higher number of inflammatory cells infiltrating from mucosa to serosa of the colons in oxazolone-treated CIITA-Tg mice, compared with wild type controls (Fig. 4B).

Bottom Line: The MHC class II transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC class II restricted antigen presentation.Previously we suggested another role of CIITA in Th1/Th2 balance by demonstrating that forced expression of CIITA in murine T cells repressed Th1 immunity both in vitro and in vivo.And, CD4+ T cells from the mesenteric lymph node of CIITA-transgenic mice treated with oxazolone exhibited a high level of IL-4 secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Hallym University College of Medicine, Chuncheon, Korea.

ABSTRACT
The MHC class II transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC class II restricted antigen presentation. Previously we suggested another role of CIITA in Th1/Th2 balance by demonstrating that forced expression of CIITA in murine T cells repressed Th1 immunity both in vitro and in vivo. However, the results were contradictory to the report that CIITA functioned to suppress the production of Th2 cytokine by CD4+ T cells in CIITA deficient mice. In this study, we investigated the influence of constitutive expression of CIITA in T cells on Th2 immune response in vivo using murine experimental colitis model. In the dextran sodium sulfate-induced acute colitis, a disease involving innate immunity, CIITA transgenic mice and wild type control mice showed similar progression of the disease. However, the development of oxazolone-induced colitis, a colitis mediated by predominantly Th2 immune response, was aggravated in CIITA-transgenic mice. And, CD4+ T cells from the mesenteric lymph node of CIITA-transgenic mice treated with oxazolone exhibited a high level of IL-4 secretion. Together, these data demonstrate that constitutive expression of CIITA in T cells skews immune response to Th2, resulting in aggravation of Th2-mediated colitis in vivo.

Show MeSH
Related in: MedlinePlus