| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 3257037 | Clinical Immunology | 2012 | 11 Pages |
MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4+ T, CD8+ T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ and decreased numbers of not only NK cells but also CD4+ T and CD8+ T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells.
► Endogenous Spred-2 was increased in the liver after APAP challenge. ► Spred-2 knockout mice demonstrated exacerbated APAP-hepatotoxicity. ► The exacerbated liver injury was likely due to the increased hepatotoxic-lymphocytes. ► Coordinated action of NK cells and Kupffer cells appeared to be important.
