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Title: Regulation of Intestinal Inflammation by Mitogen-Activated Protein Kinase Phosphatase-3
Keywords: MKP-3, DUSP6, KLF5, intestinal epithelia, intestinal inflammation, DSS-induced colitis model
Issue Date: 20-Dec-2013
Citation: SUZAN SAIDIN (2013-12-20). Regulation of Intestinal Inflammation by Mitogen-Activated Protein Kinase Phosphatase-3. ScholarBank@NUS Repository.
Abstract: During intestinal inflammation, the disruption of the intestinal mucosa barrier enabled the luminal microbiota to come into direct contact with the underlying immune cells, which results in inflammatory response. The recognition of the luminal microbiota by the Toll-like receptors (TLRs) activates downstream signalling pathways such as the mitogen-activated protein kinase (MAPK). The MAPK pathway is essential in regulating immune response and its negative regulation is controlled by MAPK phosphatases (MKPs). MKP-3, also known as DUSP6, is a MAPK phosphatase with high specificity towards ERK, which is known to regulate cell proliferation. The role of MKPs in immune cells has been widely studied but the role of MKPs in the intestinal epithelial cells (IEC) during intestinal inflammation has yet to be explored. In this study, we utilised CMT93 cells overexpressing MKP-3 and dextran sodium sulphate (DSS)-induced colitis model in mice deficient in MKP-3 to investigate the role of MKP-3 in intestinal inflammation. The results showed that overexpression of MKP-3 downregulated the phosphorylation of all three major groups of MAPKs (ERK, JNK and p38) and pro-inflammatory gene expression upon DSS and LPS stimulation. In addition, the overexpression of MKP-3 retarded cell proliferation and wound healing ability of CMT93 cells. MKP-3-/- mice subjected to 7 days of DSS treatment developed less severe colitis compared to the wildtype mice. mRNA and protein analysis showed that the expression of pro-inflammatory genes was reduced and the phosphorylation of ERK was increased in the colon of MKP-3-/- mice. The expression of proliferation genes and Kru?ppel-like transcription factor 5 (KLF5) protein was also elevated in the colon of MKP-3-/- mice. In addition, Ki67 staining showed increased IEC proliferation in the colon of MKP-3-/- mice. These results suggested the role of MKP-3 in IEC during intestinal inflammation by affecting inflammatory gene expression, IEC proliferation and restitution.
Appears in Collections:Master's Theses (Open)

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