항기저막사구체신염에서 Clin three-requiring 9과 Th17 경로 유발 염증과의 관계

학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2017. 2. 진호준.T helper 17 (Th17) lymphocytes promote renal inflammation in anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), and signal transducer and activator of transcription 3 (STAT3) mediates activation of Th17 lymphocytes by interleukin 6 (IL-6) and transforming growth factor beta (TGFβ). Clin three requiring 9 (Ctr9), a subunit of RNA polymerase-associated factor complex (PAFc), regulates the transcription of IL-6/STAT3-dependent genes. Here, the role of Ctr9 in regulating Th17-driven inflammation was investigated in anti-GBM GN. In mice, STAT3β or IL-17 knockout ameliorated anti-GBM autoantibody-induced renal injury. This phenomenon was associated with decreases in retinoic acid receptor-related orphan receptor γt (RORγt), IL-17, phosphorylated STAT3, and pro-inflammatory cytokines. Compared with wild-type mice, Ctr9 increased in both STAT3β-/- and IL-17-/- mice injected with anti-GBM IgG, showing a negative correlation with Th17-related transcripts. Small interfering RNA (siRNA)-mediated knockdown of Ctr9 in intrarenal lymphocytes further upregulated Th17-related transcripts, consistent with repression of Th17 differentiation by Ctr9. Interestingly, Ctr9 was also expressed in human and mouse mesangial cells and downregulated in response to anti-GBM IgG or to TGFβ plus IL-17. Ctr9 in mesangial cells was even more repressed in the presence of both anti-GBM IgG and Th17-activating cytokines. Consistent with these findings, renal biopsies obtained from patients with anti-GBM GN showed consistent downregulation of Ctr9 and upregulation of phosphorylated STAT3 and IL-17 in the glomerulus. In this study, Ctr9 is associated with suppression of Th17 differentiation in anti-GBM GN and repressed by anti-GBM IgG and IL-17 in mesangial cells. This is the first study to examine the association between Ctr9 and Th17 driven renal inflammation in anti-GBM GN. Further study should be considered to clarify whether Ctr9 has an impact on Th17 pathway as a transcriptional regulator in anti-GBM GN.Introduction 1 MATERIALS AND METHODS 11 RESULTS 23 DISCUSSION 65 REFERENCES 71 국문초록 79Docto