title: Effect of recombinant α1-antitrypsin Fc-fused (AAT-Fc)protein on the inhibition of inflammatory cytokine production and streptozotocin-induced diabetes.
abstract: α1-Antitrypsin (AAT) is a member of the serine proteinase inhibitor family that impedes the enzymatic activity of serine proteinases, including human neutrophil elastase, cathepsin G and neutrophil proteinase 3. Here, we expressed recombinant AAT by fusing the intact AAT gene to the constant region of IgG1 to generate soluble recombinant AAT-Fc protein. The recombinant AAT-Fc protein was produced in Chinese hamster ovary (CHO) cells and purified using mini-protein A affinity chromatography. Recombinant AAT-Fc protein was tested for antiinflammatory function and AAT-Fc sufficiently suppressed tumor necrosis factor (TNF)-α-induced interleukin (IL)-6 in human peripheral blood mononuclear cells (PBMCs) and inhibited cytokine-induced TNFα by different cytokines in mouse macrophage Raw 264.7 cells. However, AAT-Fc failed to suppress lipopolysaccharide-induced cytokine production in both PBMCs and macrophages. In addition, our data showed that AAT-Fc blocks the development of hyperglycemia in a streptozotocin-induced mouse model of diabetes. Interestingly, we also found that plasma-derived AAT specifically inhibited the enzymatic activity of elastase but that AAT-Fc had no inhibitory effect on elastase activity.
authors.affiliation: Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
authors.forename: Siyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Youngmin
authors.initials: Y
authors.lastname: Lee
authors.forename: Kwangwon
authors.initials: K
authors.lastname: Hong
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Hong
authors.forename: Suyoung
authors.initials: S
authors.lastname: Bae
authors.forename: Jida
authors.initials: J
authors.lastname: Choi
authors.forename: Hyunjhung
authors.initials: H
authors.lastname: Jhun
authors.forename: Areum
authors.initials: A
authors.lastname: Kwak
authors.forename: Eunsom
authors.initials: E
authors.lastname: Kim
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Jo
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010196:Pancreatic Elastase / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase
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