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An example is infectious mononucleosis caused by primary infection with EBV. Previously, we demonstrated that airway infection of mice with murine \u03b3-herpesvirus 68 (MHV68), a murine model of EBV, caused liver inflammation with elevated serum liver enzymes and intrahepatic infiltration of IFN-\u03b3\u2013producing CD8+ T cells and NK cells. Mechanistically, the expression of the CXCR3-ligand chemokines, which are commonly induced by IFN-\u03b3 and attract IFN-\u03b3\u2013producing Th1-type cells via CXCR3, was upregulated in the liver. Importantly, the liver inflammation was suppressed by oral neomycin, an intestine-impermeable aminoglycoside, suggesting an involvement of some products from the intestinal microbiota. In this study, we showed that the liver inflammation and the expression of the CXCR3-ligand chemokines in the liver were effectively ameliorated by i.p. administration of anti-TLR4 mAb or C34, a TLR4 blocker, as well as in TLR4-deficient mice. Conversely, intrarectal inoculation of Escherichia coli as an extraintestinal source of LPS aggravated liver inflammation in MHV68-infected mice with increased expression of the CXCR3-ligand chemokines in the liver. In contrast, the lung inflammation in MHV68-infected mice was not affected by oral neomycin, i.p. administration of C34, or TLR4 deficiency. Collectively, the LPS\u2013TLR4 pathway plays a pivotal role in the liver inflammation of MHV68-infected mice at least in part by upregulating the CXCR3-ligand chemokines in the liver.<\/jats:p>","DOI":"10.4049\/jimmunol.2200653","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T13:02:01Z","timestamp":1695992521000},"page":"1550-1560","source":"Crossref","is-referenced-by-count":4,"title":["Involvement of TLR4 in Acute Hepatitis Associated with Airway Infection of Murine \u03b3-Herpesvirus 68"],"prefix":"10.1093","volume":"211","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7984-207X","authenticated-orcid":false,"given":"Kyosuke","family":"Kanai","sequence":"first","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Faculty of Medicine, Tottori University , Yonago, Tottori ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-6137","authenticated-orcid":false,"given":"Seiji","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Faculty of Medicine, Tottori University , Yonago, Tottori ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4353-5809","authenticated-orcid":false,"given":"Osamu","family":"Yoshie","sequence":"additional","affiliation":[{"name":"Health and Kampo Institute , Sendai, Miyagi ,","place":["Japan"]},{"name":"Aoinosono Sendai Izumi Long-Term Health Care Facility , Sendai, Miyagi ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"2025020406183986200_r1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nrc1452","article-title":"Epstein-Barr virus: 40 years on","volume":"4","author":"Young","year":"2004","journal-title":"Nat. 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