Secreted IL-1α promotes T-cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride-induced liver injury in mice

Interleukin-1 alpha is mainly expressed on the cell membrane, but can also be secreted during inflammation. The roles of secreted and membrane IL-1 alpha in acute liver inflammation are still not known. Here, we examined the functions of secreted and membrane IL-1 alpha in a mouse model of carbon tetrachloride-induced acute liver injury. We show that secreted IL-1 alpha aggravates liver damage and membrane IL-1 alpha slightly protects mice from liver injury. Further studies showed that secreted IL-1 alpha promotes T-cell activation. It also increased the expansion of CD11b(+)Gr1(+) myeloid cells, which may serve as a negative regulator of acute liver inflammation. Moreover, secreted IL-1 alpha induced IL-6 production from hepatocytes. IL-6 neutralization reduced the proliferation of CD11b(+)Gr1(+) myeloid cells in vivo. CCL2 and CXCL5 expression was increased by secreted IL-1 alpha in vitro and in vivo. Antagonists of the chemokine receptors for CCL2 and CXCL5 significantly reduced the migration of CD11b(+)Gr1(+) myeloid cells. These results demonstrate that secreted and membrane IL-1 alpha play different roles in acute liver injury. Secreted IL-1 alpha could promote T-cell activation and the recruitment and expansion of CD11b(+)Gr1(+) myeloid cells through induction of CCL2, CXCL5, and IL-6. The controlled release of IL-1 alpha could be a critical regulator during acute liver inflammation.