AIMP1/p43 Protein Induces the Maturation of Bone Marrow-Derived Dendritic Cells with T Helper Type 1-Polarizing Ability

Abstract

AIMP1 (ARS-interacting multifunctional protein 1), previously known as p43, was initially identified as a factor associated with a macromolecular tRNA synthetase complex. Recently, we demonstrated that AIMP1 is also secreted and acts as a novel pleiotropic cytokine. In this study, we investigated whether AIMP1 induces the activation and maturation of murine bone marrow-derived dendritic cells (DCs). AIMP1-treated DCs exhibited up-regulated expression of cell-surface molecules, including CD40, CD86, and MHC class II. Additionally, microarray analysis and RT-PCR determinations indicated that the expression of known DC maturation genes also increased significantly following treatment with AIMP1. Treatment of DCs with AIMP1 resulted in a significant increase in IL-12 production and Ag-presenting capability, and it also stimulated the proliferation of allogeneic T cells. Importantly, AIMP1-treated DCs induced activation of Ag-specific Th type 1 (Th1) cells in vitro and in vivo. AIMP1-stimulated DCs significantly enhanced the IFN-γ production of cocultured CD4+ T cells. Immunization of mice with keyhole limpet hemocyanin-pulsed AIMP1 DCs efficiently led to Ag-specific Th1 cell responses, as determined by flow cytometry and ELISA. The addition of a neutralizing anti-IL-12 mAb to the cell cultures that had been treated with AIMP1 resulted in the decreased production of IFN-γ, thereby indicating that AIMP1-stimulated DCs may enhance the Th1 response through increased production of IL-12 by APCs. Taken together, these results indicate that AIMP1 protein induces the maturation and activation of DCs, which skew the immune response toward a Th1 response.

Aminoacyl tRNA Synthetase–Interacting Multifunctional Protein 1 Acts as a Novel B Cell–Activating Factor In Vitro and In Vivo

“…AIMP1 is also secreted and has been shown to have various activities, including effects on wound healing (10) and glucagon-like functions that control blood glucose levels (11). Furthermore, we demonstrated that AIMP1 functions as a proinflammatory cytokine that induces macrophage activation, DC maturation, and IL-12 production, indicating that AIMP1 is a novel immune modulator (12,13). However, it is unclear whether AIMP1 affects other APCs, such as B cells.…”

“…The in vivo administration of AIMP1 induced CD69 expression on splenic B cells, indicating that AIMP1 is a critical B cell activator. We previously reported that AIMP1 activates macrophages and DCs (12,13). Because stimulated macrophages and DCs are known to express BAFF and APRIL (18), the in vivo data might be, at least in part, mediated by these cells.…”

“…AIMP1 is a good candidate for vaccination because it directly activates macrophages (12), DCs (13), and B cells. Our results also showed that AIMP1 enhanced Ab production (Fig.…”

“…We measured CD69 expression, an early activation marker, to determine the direct B cell-activating effects of AIMP1 and to exclude DC-mediated B cell activation, because AIMP1 is known to induce the activation and maturation of DCs (13). Spleens and blood samples were collected 20 h postinjection, and CD69 expression on CD19 + B cells was evaluated.…”

Aminoacyl‐tRNA synthetase–interacting multifunctional proteins (AIMPs): A triad for cellular homeostasis

“…2A). Although AIMP1 is mainly bound to the multi-tRNA synthetase complex, it is also secreted on hypoxia or cytokine stimulation and works as a cytokine on various target cells such as endothelial cells, monocyte/macrophage, dendritic cells (DCs), fibroblasts, and pancreatic a cells (23)(24)(25)(26)(27)(28). The secreted AIMP1 controls angiogenesis depending on its local concentration.…”