Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4 and CD8 T cells.

Introduction: Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown.

Objectives: We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model.

Methods: We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry.

Results: Spred2-deficient mice (Spred2) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2 mice, and pretreatment of Spred2 mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2 mice. IFNγ was mainly produced from CD4 and CD8 T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4 and/or CD8 T cells from Spred2 mice into RAG1 mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2 mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4 and CD8 T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4 and CD8 T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A .

Conclusion: We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.