Differential gene expression in Behcet's disease and differential anti-tumor effects of Tim3 pathway blocking molecules

PART I Differential expression of genes according to colchicine responsiveness in Behçet’s disease Behçet disease (BD) is a chronic relapsing, systemic inflammatory disorder which is treated with colchicine. However, some patients are not responsive to it. In this study, I wanted to explore the biomarkers to distinguish colchicine responsiveness. I stimulated peripheral blood mononuclear cells (PBMCs) and CD11b+ cells of BD patients with lipopolysaccharide (LPS) and analyzed the expression of inflammatory cytokines, transcription factors and microRNAs. Compared to colchicine-responsive BD patients (BDR), the expression of IL-6 and TNF-α were significantly increased in colchicine-non-responsive BD patients (BDNR) in both the basal and LPS-stimulated states. Concordantly, the expression of C/EBPδ, C/EBPβ transactiption factor of IL-6, was significantly upregulated in BDNR compared to BDR. Also, the expression of ATF-3 transcript was significantly increased in BDR compared to BDNR. The link of dyregulation in these transcription factors to abnormal cytokine production in BD was also demonstrated. Finally, I found the differential expression of miR-638, miR-4488, miR-3591-3p in BD according to colchicine responsiveness. My results suggest that these molecules might be useful to predict colchicine responsiveness in BD. PART II Differential anti-tumor effects of three forms of Tim-3 pathway blocking molecules Tim-3 is a molecule containing T cell immunoglobulin variable region (IgV)-like domain and mucin-domain, and known to suppress Th-1 immune response. In a previous study, blocking Tim3 pathway increases anti-tumor immunity leading to tumor growth suppression. In this study, I evaluated the tumor suppressive effect of three different molecules blocking Tim3 pathway: Tim3 IgV like domain alone (Tim3V), fusion protein of Tim3V with mouse immunoglobulin CH2CH3 (Tim3VmIg) and its dimer (Tim3VdIg). Both TimVmIg and Tim3VdIg suppress tumor growth but T3V did not. Compared to control Tim3VdIg but not Tim3V reduced frequency of myeloid derived suppressor cells (MDSCs) in splenocytes of mice on 21 day after tumor challenge. These results indicate that Tim3V domain alone is not sufficient for tumor growth suppression but is in the presence of its fusion partner of immunoglobulin CH2CH3.

Author dc:creator

• 우, 민영

Contributors dc:contributor

• 박, 선
• 대학원 의생명과학과
• 200824572

• Behçet’s disease
• colchicine
• LPS
• IL-6
• TNF-α
• C/EBP-β
• C/EBP-δ
• ATF3
• microRNA
• Tim3 pathway
• tumor
• MDSCs
• Tim3 경로 차단 분자
• 종양
• myeloid derived suppressor cells

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000014776
000000014776

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/8598