Interleukin-18 binding protein (IL-18BP) is a natural IL-18 inhibitor in vivo, which can effectively neutralize IL-18 and inhibit the inflammatory signaling pathway induced by IL-18, thus playing an anti-inflammatory role. Traditional production methods primarily rely on eukaryotic animal cell expression systems, which often entail complex processes, lower yields, and increase production costs. In this study, we present a novel approach for expressing IL-18BP fusion protein using the Escherichia coli (E. coli) system. The N-terminal segment of IL-18BP was fused with the small ubiquitin-related modifier (SUMO) tag, enabling soluble expression, while the C-terminal segment was fused with the human IgG1 Fc fragment to prolong its in vivo lifespan. Through screening, we obtained a high-expression engineering strain from a single colony and developed optimized protocols for fermentation and purification of the recombinant SUMO-IL-18BP-Fc protein. The SUMO tag was subsequently cleaved using SUMO protease, and the purified recombinant human IL-18BP-Fc (rhIL-18BP-Fc) exhibited a purity exceeding 90% with a yield of 1 g per liter of bacterial solution. The biological activities and underlying mechanisms of rhIL-18BP-Fc were evaluated using cell lines and a mouse model. Our results demonstrated that rhIL-18BP-Fc effectively inhibited IL-18-stimulated IFN-γ production in KG-1a cells in vitro and ameliorated DSS-induced ulcerative colitis in mice. In conclusion, we successfully employed the SUMO fusion system to achieve high-level production, soluble expression, and prolonged activity of rhIL-18BP-Fc in E. coli. These findings lay the groundwork for future large-scale industrial production and pharmaceutical development of rhIL-18BP-Fc protein. KEY POINTS: • Effective expression, fermentation, and purification of bioactive rhIL-18BP-Fc protein in E. coli. • The rhIL-18BP-Fc protein has a great potential for the therapy of ulcerative colitis by inhibiting the expression of inflammatory factors.

01 Nov 2014·Clinical and Experimental MedicineQ3 · MEDICINE

Effect of hydrodynamics-based delivery of IL-18BP fusion gene on rat experimental autoimmune myocarditis

Q3 · MEDICINE

Article

Author: He Chang ; Haruo Hanawa ; Le Zhang ; Jun Zou ; Yan Chun Liao ; Yan Wang ; Gang Li ; Guang Wei Zhang

Interleukin-18 (IL-18) is a powerful and important cytokine in myocarditis. IL-18-binding protein (IL-18BP), a naturally occurring antagonist of IL-18, is presumed to play a vital regulatory function in IL-18-mediated immune responses. The purpose of this study was to evaluate the alterations of IL-18 and its related protein expressions and the effect of hydrodynamics-based delivery of the IL-18BP gene for treatment of rat experimental autoimmune myocarditis (EAM).Rats were immunized on Day 0 and killed on 2, 3 and 4 weeks to determine IL-18 and its related protein expression and target cells in EAM hearts. On Day 6, rats were injected with a recombinant plasmid encoding IL-18BP-Ig or SP-Ig. On Day 17, rats were detected with echocardiography and then be killed. IL-18BP gene therapy was effective in controlling EAM, as monitored by a decreased ratio of heart weight to body weight, reduced myocarditis areas, reduced expression of atrial natriuretic peptide, brain natriuretic peptide, IL-17, IFN-γ, IL-6 and IL-10. Furthermore, the effect of serum containing IL-18BP on the expression of immune-relevant genes in IL-1α-stimulated NC cells and splenocytes cultured from EAM rats was examined. The results showed that IL-18BP significantly suppressed the expression of IL-17 as well as other proinflammatory genes such as transforming growth factor-β, prostaglandin E2 synthase, cyclooxygenase-2 in IL-1α-stimulated NC cells, and IL-18BP also significantly suppressed the expression of IL-17, IL-17R, IL-21 and IL-17-related transcriptional factor retinoic acid-related orphan nuclear receptor, signal transducer and activator of transcription-3 and Foxp3 in IL-1α-stimulated splenocytes cultured from EAM rats. IL-18 and its related protein played an important role on the development of EAM. IL-18BP effectively prevented progression of EAM by blocking IL-17 and related inflammatory genes expression. This might be a possible mechanism of the amelioration of EAM by IL-18BP treatment.

01 Oct 2014·Die Pharmazie

Cardiovascular protective effects of IL-1 ra-Fc-IL-18BP on experimental myocardial infarction by inhibiting oxidative stress and inflammation in a rat model.

Article

Author: Xie, Haolin ; Sui, Dayun ; Zhang, Hong ; Xu, Huali ; Yu, Xiaofeng ; Li, Feng

In this study, we examined the cardiovascular protective effects of IL-1ra-Fc-IL-18BP on experimental myocardial infarction in a rat model. An animal model of myocardial infarction (MI) was induced by permanent ligation of the left anterior descending coronary artery (LAD) in SD rats. After surgery sixty male rats and sixty female rats were randomly divided into groups as followed: sham group, MI group, IL-1ra-Fc-IL-18BP 50,100, 200 mg/kg treatment groups, and verapamil 5 mg/kg treatment group. IL-1 ra-Fc-IL-18BP and verapamil were administered to the animals immediately after operation by intravenous injection. Treatment with IL-1ra-Fc-IL-18BP (50, 100 and 200 mg/kg) could remarkably decrease infarct size from 24.82% to 13.43% (p < 0.05), and decrease the activities of serum aspartate aminotransferase (AST), creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) compared with sham group (p < 0.05). Meanwhile, treatment with IL-1ra-Fc-IL-18BP (200 mg/kg) could significantly increase the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), but decreased the content of malondiadehyde (MDA) in serum (p < 0.05). Furthermore, IL-1ra-Fc-IL-18BP marablely reduced the content of calcium (Ca2+) in serum (p < 0.05), and also decreased the levels of serum interleukin-1β (IL-1β), tumor necrosis factor (TNF-α) (p < 0.05). Histopathological results demonstrated the same protective effect of IL-1ra-Fc-IL-18BP All these results above indicated that IL-1ra-Fc-IL-18BP has protective effects in myocardial infarction, improves free radicals metabolism, ameliorates myocardial calcium overload and inhibits the release of inflammatory cytokines.

100 Deals associated with AMP18P1RA

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Ischemia	Discovery	US	Amprotein Corp.	-
Neoplasms	Discovery	US	Amprotein Corp.	-
Psoriasis	Discovery	US	Amprotein Corp.	-

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