Studies on the identification of a functional receptor and its signal transduction mechanism involving AIMP1-induced TNF production in immune cells
면역세포에서 AIMP1에 의해 유도되는 TNF 생산 관련 수용체 규명 및 신호 전달 기작에 관한 연구
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과(의약생명과학전공), 2012. 8. 김성훈.
- ARS-interacting multifunctional protein 1 (AIMP1/p43) can be secreted to trigger proinflammatory molecules while it is predominantly bound to a cytoplasmic macromolecular protein complex that contains several different aminoacyl-tRNA synthetases. Although its activities as a secreted signaling factor have been well-characterized, the functional receptor for its proinflammatory activity has not yet identified. In this study, I have identified the receptor molecule for AIMP1 that mediates the secretion of TNF-alpha from THP-1 monocytic cells and primary human peripheral blood mononuclear cells (PBMCs). In a screen of 499 soluble receptors, I identified CD23, a known low-affinity receptor for IgE, as a high affinity binding partner of AIMP1. I found that down-regulation of CD23 attenuated AIMP1-induced TNF-alpha secretion and AIMP1 binding to THP-1 and PBMCs. I also observed that in THP-1 and PBMCs, AIMP1-induced TNF-alpha secretion mediated by CD23 involved activation of ERK1/2. Interestingly, endothelial monocyte activating polypeptide II (EMAP II), the C-terminal fragment of AIMP1 that is also known to work as a proinflammatory cytokine, was incapable of binding to CD23 and of activating ERK1/2. Therefore, identification of CD23 not only explains the inflammatory function of AIMP1 but also provides the first evidence by which the mode of action of AIMP1 can be distinguished from that of its C-terminal domain, EMAP II.