The Novel Cytokine p43 Induces IL-12 Production in Macrophages via NF-κB Activation, Leading to Enhanced IFN-γ Production in CD4+ T Cells

Abstract

Recently, we determined that p43, an auxiliary factor of mammalian multiaminoacyl-tRNA synthetases, is secreted, and functions as a novel pleiotropic cytokine. In this study, we have attempted to characterize the effects of p43 on the generation of IL-12 in mouse macrophages. p43 was determined to induce significant IL-12 production from mouse macrophages in a dose-dependent manner. The stimulatory effect of p43 on the activation of IL-12p40 promoter was mapped to a region harboring an NF-κB binding site. The nuclear extracts from the p43-stimulated macrophages exhibited profound NF-κB DNA-binding activity, as determined by the EMSA. In addition, the p43-stimulated IL-12 induction and NF-κB DNA-binding activity were significantly suppressed by caffeic acid phenethyl ester and BAY11-7082, both inhibitors of NF-κB activation, indicating that p43 induced the production of IL-12 in macrophages mainly via the activation of NF-κB. Importantly, p43 increased the level of IFN-γ production in the Ag-primed lymph node cells, but had no effect on IL-4 levels. The addition of a neutralizing anti-IL-12p40 mAb to the cell cultures resulted in a decrease of the production of p43-enhanced IFN-γ by the keyhole limpet hemocyanin-primed lymph node cells. Furthermore, coincubation with p43-pretreated macrophages enhanced the production of IFN-γ by the keyhole limpet hemocyanin-primed CD4+ T cells, thereby indicating that p43 may enhance IFN-γ expression in CD4+ T cells via the induction of IL-12 production in macrophages. These results indicate that p43 may play an essential role in the development of the Th1 immune responses associated with cancer immunotherapy and protective immunity against intracellular pathogens.

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

“…We have previously demonstrated that AIMP1 induced IL-12 production in mouse macrophages via the activation of NF-B (20). Consistent with these results, AIMP1 significantly increased the binding of the NF-B transcription factor to the B site in DCs, as measured by an electrophoretic mobility assay (data not shown).…”

“…Previously we found that AIMP1 stimulated macrophages to secrete IL-12, and that AIMP1-activated macrophages induced the IFN-␥ production from keyhole limpet hemocyanin (KLH)-primed Th cells (20). It is not clear at present whether AIMP1 is involved in the maturation and activation of DCs, which lead to regulate T cell responses.…”

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

“…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 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.…”

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

“…AIMP1 stimulates monocytes/macrophages via activation of p38 MAPK, ERK, and NFjB, inducing secretion of proinflammatory cytokines such as tumor necrosis factor-a (TNFa), interleukin-8 (IL-8), and macrophage chemotactic protein-1 (24,29,30). AIMP1 also induces maturation of DCs and enhances production of IL-6 and IL-12 which are critical cytokines for the suppression of cancer prevalence (31). With this immune stimulatory activity, systemic infusion of AIMP1 into nude mice harboring human cancer cell line suppressed tumor growth through activation of immune system (32).…”