Major histocompatibility class II (MHC II) -specific activation of CD4(+) T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STATI phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFN gamma. Furthermore, inhibition of ERK signaling decreased the phosphorylation of STAT1, as well as the production of MHC II in vivo and in vitro. These findings suggest that STATI contributes to bone cancer pain as a downstream mediator of ERK signaling by regulating MHC II expression in spinal microglia. (C) 2016 Elsevier Inc. All rights reserved.