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Inhibition of myeloid differentiation 1 specifically in colon with antisense oligonucleotide exacerbates dextran sodium sulfate-induced colitis
Authors:Xiaoxing Chen  Huaqin Pan  Jin Li  Guqin Zhang  Shizhe Cheng  Na Zuo  Qiu Zhao  Zhiyong Peng
Institution:1. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China;2. Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China;3. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China

Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, Hubei, People's Republic of China;4. Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China;5. Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, People's Republic of China

Abstract:Myeloid differentiation 1 (MD-1), also known as lymphocyte antigen 86 (Ly86), is a soluble protein homologous to MD-2 and forms a complex with radioprotective 105 (RP105). RP105/MD-1 complex negatively regulates toll-like receptor 4 (TLR4) signaling and is involved in several immune disorders. However, the precise role of MD-1 in inflammatory bowel diseases (IBD) remains poorly understood. To further investigate the involvement of MD-1 in IBD, we inhibited MD-1 in colon with antisense oligonucleotide (AS-ODN) and assessed the effect of MD-1 inhibition on dextran sodium sulfate (DSS)-induced colitis. We discovered that MD-1 protein expression was remarkably decreased in both patients with ulcerative colitis and mice with DSS-induced colitis. For the first time, we showed that oral administration of MD-1 AS-ODN to mice significantly suppressed the MD-1 protein levels in colon rather than systemic tissues. Subsequently, we found that MD-1 AS-ODN treated mice were more susceptible to DSS-induced colitis based on loss of body weight, colon length, histological scores, and disease activity index. MD-1 inhibition also significantly enhanced inflammatory cytokines production such as IL-6 and IL-1β in colons. Finally, mice treated with MD-1 AS-ODN exhibited increased messenger RNA levels of TLR4 and MyD88 after DSS exposure and showed enhanced nuclear factor (NF)-κB activation compared with the control. Taken together, specifically suppression of MD-1 in colon tissues with AS-ODN exacerbates DSS-induced experimental colitis in mice, which is possibly related to activation of TLR4/NF-κB signaling.
Keywords:antisense oligonucleotide  colitis  dextran sodium sulfate  myeloid differentiation 1  NF-κB
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