Abstract
This study investigated the mechanism of protein disulfide-isomerase A3 (PDIA3)-induced visceral hypersensitivity in irritable bowel syndrome (IBS). Rats were treated with saline (control), acetic acid and restraint stress (IBS model), empty vector (RNAi control) and PDIA3-RNAi vector (PDIA3-RNAi). Mesenteric lymph node DCs (MLNDCs) and splenic CD4+/CD8+ T cells were isolated for co-cultivation. Compared with control, MLNDCs co-cultured with CD4+ or CD8+ T cells showed an increased ability to promote T cell proliferation and produced more IL-4 or IL-9 secretion. Compared with the RNAi control, MLNDCs from the PDIA3 knockdown models were less effective in promoting the proliferation of CD4+/CD8+ T cells. It is concluded that PDIA3 plays an important role in the development of IBS through the DC-mediated activation of T cells, resulting in degranulation of MCs and visceral hypersensitivity.
Highlights
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders characterized by the presence of abdominal pain or discomfort and associated with altered bowel habits, causing significant heathy issue globally (Spiegel, 2009)
We found that the expression of protein disulfide-isomerase A3 (PDIA3), a member of protein disulfide-isomerase family, is significantly upregulated in the colon mucosa tissues of IBS rats (Ding et al, 2010), suggesting that PDIA3 may be involved in IBS pathogenesis
In the PDIA3-RNAi models, the number of ileocecal dendritic cells (DCs) was reduced and these DCs were less effective in promoting T cell proliferation. These results suggest that DC may play an important role in the formation of visceral hypersensitivity in IBS by the activation of spleen CD4+/CD8+ to produce excessive IL-4 and IL-9 under local or systemic stress; knockdown of PDIA3 expression reduces the number and activity of intestinal DCs in visceral hypersensitivity rats, inhibits the abnormal increase of mast cell (MC) in serum and colon and the activity of abnormally secreted cytokines
Summary
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders characterized by the presence of abdominal pain or discomfort and associated with altered bowel habits, causing significant heathy issue globally (Spiegel, 2009). The causes and pathogenesis of IBS are still largely unclear. A growing number of studies suggest that immune dysregulation is closely related to the pathogenesis of IBS and mucosal immune dysfunction plays an important role in the pathogenesis of IBS. Studies have shown that the infiltration and release of mast cell (MC) in colon are the cause of the symptom in IBS patients, and are closely related to visceral hypersensitivity in patients with IBS (Ohman & Simren, 2010).
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