Lysyl-Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-kappa B Pathways, Strongly Contributing to Enhanced Th1 Cell Responses

초록

In addition to essential roles in protein synthesis, lysyl-tRNA synthetase (KRS) is secreted to trigger a proinflammatory function that induces macrophage activation and TNF-alpha secretion. KRS has been associated with autoimmune diseases such as polymyositis and dermatomyositis. In this study, we investigated the immunomodulatory effects of KRS on bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and subsequent polarization of Th cells and analyzed the underlying mechanisms. KRS-treated DCs increased the expression of cell surface molecules and proinflammatory cytokines associated with DC maturation and activation. Especially, KRS treatment significantly increased production of IL-12, a Th1-polarizing cytokine, in DCs. KRS triggered the nuclear translocation of the NF-kappa B p65 subunit along with the degradation of I kappa B proteins and the phosphorylation of MAPKs in DCs. Additionally, JNK, p38, and ERK inhibitors markedly recovered the degradation of I kappa B proteins, suggesting the involvement of MAPKs as the upstream regulators of NF-kappa B in the KRS-induced DC maturation and activation. Importantly, KRS-treated DCs strongly increased the differentiation of Th1 cells when cocultured with CD4(+ )T cells. The addition of anti- IL-12-neutralizing Ab abolished the secretion of IFN-gamma in the coculture, indicating that KRS induces Th1 cell response via DC-derived IL-12. Moreover, KRS enhanced the OVA-specific Th1 cell polarization in vivo following the adoptive transfer of OVA-pulsed DCs. Taken together, these results indicated that KRS effectively induced the maturation and activation of DCs through MAPKs/NF-kappa B-signaling pathways and favored DC-mediated Th1 cell response.

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