Murine gamma-Herpesvirus 68 Induces Severe Lung Inflammation in IL-27 Deficient Mice with Liver Dysfunction Preventable by Oral Neomycin

作者：Kanai Kyosuke; Park Ah Mee; Watanabe Akiko; Arikawa Tomohiro; Yasui Teruhito; Yoshida Hiroki; Tsunoda Ikuo; Yoshie Osamu

来源：The Journal of Immunology, 2018, 200(8): 2703-2713.

DOI：10.4049/jimmunol.1700412

IL-27 is an immunoregulatory cytokine consisting of p28 and EBI3. Its receptor also has two subunits, WSX1 and gp130. Although IL-27 promotes Th1 differentiation in naive T cells, it also induces IL-10 expression in effector Th1 cells to curtail excessive immune responses. By using p28-deficient mice and WSX1-deficient mice (collectively called IL-27 deficient mice), we examined the role of IL-27 in primary infection by murine gamma-herpesvirus 68 (MHV68), a murine model of EBV. Upon airway infection with MHV68, IL-27 deficient mice had more aggravated lung inflammation than wild-type mice, although MHV68 infection per se was better controlled in IL-27 deficient mice. Although epithelial cells and alveolar macrophages were primarily infected by MHV68, interstitial macrophages and dendritic cells were the major producers of IL-27. The lung inflammation of IL-27 deficient mice was characterized by more IFN-gamma producing CD8(+) T cells and fewer IL-10 producing CD8(+) T cells than that of wild-type mice. An infectious mononucleosis like disease was also aggravated in IL-27 deficient mice, with prominent splenomegaly and severe hepatitis. Infiltration of IFN-gamma producing effector cells and upregulation of the CXCR3 ligand chemokines CXCL9, CXCL10, and CXCL11 were noted in the liver of MHV68-infected mice. Oral neomycin effectively ameliorated hepatitis, with decreased production of these chemokines in the liver, suggesting that the intestinal microbiota plays a role in liver inflammation through upregulation of these chemokines. Collectively, IL-27 is essential for the generation of IL-10 producing effector cells in primary infection by MHV68. Our findings may also provide new insight into the mechanism of hepatitis associated with infectious mononucleosis.

• 出版日期2018-4-15