Cytomegalovirus infection initiates inflammatory bowel disease by activating a positive MyD88/NF-κB feedback loop in allogeneic skin transplantation mice

Infection with the cytomegalovirus (CMV) is common. Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract. CMV Infection is involved in IBD pathogenesis. The abnormal activation of myeloid differentiation factor 88 (MyD88)/nuclear factor- kappa B (NF-κB) signaling, which results in inflammatory cytokine overexpression, is an important factor in IBD pathogenesis. The present study aimed to examine the effect of CMV Infection on NF-κB activation and its role in IBD pathogenesis. Since BALB/c rather than C57BL/6 mice belong to the murine CMV (MCMV) susceptible strain, allogeneic skin transplantation was conducted between MyD88 (+/+) or MyD88-knockout MyD88 (-/-) BALB/c (recipient) mice and C57BL/6 (donor) mice. Thereafter, the immune function of the recipient mice was reduced by immunosuppressant cyclosporine, which is meaningful in the pathogenesis of IBD caused by MCMV in immunocompromised mice. MCMV strain K181-eGFP (eGFP K181) or hMIEP-eGFP K181 (knockout MCMV IE1-3 promoter) was used to infect MyD88 (+/+) BALB/c mice while eGFP K181 was also used to infect MyD88 (-/-) BALB/c mice on day 14 post allogeneic skin transplantation. MCMV DNA was detected via nested polymerase chain reaction. Hematoxylin-Eosin staining was used to assess colon necrosis and inflammatory cell infiltration. The serum levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-8, IL-12, flagellin, lipopolysaccharide, and myeloperoxidase were detected by ELISA and immune reaction. Immunoblots were applied to measure protein levels. eGFP K181 Infection significantly induced colon permeability, necrosis, inflammatory cell infiltration, and inflammation in allogeneic skin transplantation mice. hMIEP-eGFP K181 Infection significantly inhibited colon permeability, necrosis, inflammatory cell infiltration, and inflammation compared with eGFP K181 Infection in allogeneic skin transplantation mice. Moreover, the MyD88-dependent NF-κB signaling pathway was involved in the pathogenesis of eGFP K181-induced colon permeability and inflammation in allogeneic skin transplantation mice. Our findings highlight the importance of CMV Infection and the MyD88/NF-κB signaling pathway in IBD and might provide a new direction for the development of drugs for IBD.

Cytomegalovirus; Immediate-early protein; Inflammatory bowel disease; Inflammatory cytokines; Myd88/NF-κB.