We detected the expression of IL-12 p40/p35 mRNA by semi-quantitative RT-PCR and silver staining, and studied the molecular interaction between the IL-12 expression and the NF-κB activation induced by LPS and IFN-γ/...We detected the expression of IL-12 p40/p35 mRNA by semi-quantitative RT-PCR and silver staining, and studied the molecular interaction between the IL-12 expression and the NF-κB activation induced by LPS and IFN-γ/LPS in murine peritoneal suppressor macrophages (MPSMs). It was found that IFN-γ strongly enhanced the LPS-induced IL-12 p40 and p35 mRNA expression. Both p40 and p35 mRNA levels were approximately equal. IFN-γ also greatly promoted the LPS-induced secretion of IL-12 p70 in MPSMs. The Proteasome Inhibitor I (PSI) could block the expression of IL-12 p40 and p35 mRNA, and the degradation of κBα induced by LPS or LPS/IFN-γ. EMSA showed that LPS could augment the NF-κB binding activity to p40 promoter DNA. However, IFN-γ could neither enhance the LPS-induced NF-κB activity nor promote the degradation of kBa. Taken together, the data suggest: (i) IFN-γ/LPS could strongly induce the expression of IL-12 p40 and p35 mRNA; both the expression levels were equal; this phenomenon coincided with the high-level secretion of IL-12 p70 induced by IFN-γ/LPS; (ii) NF-KB signal pathway is essential for IFN-γ/LPS to induce IL-12 mRNA expression; (iii) by blocking the degradation of κB, the PSI suppresses the IL-12 p40/p35 mRNA expression induced by LPS and IFN-γ/LPS; (iv) NF-KB signal may not be involved in the mechanism by which IFN-γ enhanced the expression of the LPS-induced IL-12 p40/p35 mRNA.展开更多
目的:探讨白细胞介素(interleukin,IL)-12p40、干扰素(interferon,IFN)-γ在缓解复发型多发性硬化(relap-sing remitting form of multiple sclerosis,RRMS)发病中的病生机制。方法:选取RRMS急性期患者24例及作为对照组的非炎性神经系...目的:探讨白细胞介素(interleukin,IL)-12p40、干扰素(interferon,IFN)-γ在缓解复发型多发性硬化(relap-sing remitting form of multiple sclerosis,RRMS)发病中的病生机制。方法:选取RRMS急性期患者24例及作为对照组的非炎性神经系统疾病(non-inflammatory neurological diseases,NIND)患者12例,应用ELISA法测定受试者血清及脑脊液中IL-12p40、IFN-γ水平。结果:RRMS组血清中IL-12p40水平明显下降,IFN-γ水平与NIND组相比无统计学意义。脑脊液中IL-12p40、IFN-γ水平在两组中可检测到的阳性例数均低,相比之下无统计学意义。结论:IL-12p40参与了多发性硬化发病的免疫病理过程。展开更多
therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL12p40)has been established both in vitro and in vivo,warranting a first-in-human investigation in psoriasis. This pha...therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL12p40)has been established both in vitro and in vivo,warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3%body surface area involvement were enrolled infour dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75%improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.展开更多
文摘We detected the expression of IL-12 p40/p35 mRNA by semi-quantitative RT-PCR and silver staining, and studied the molecular interaction between the IL-12 expression and the NF-κB activation induced by LPS and IFN-γ/LPS in murine peritoneal suppressor macrophages (MPSMs). It was found that IFN-γ strongly enhanced the LPS-induced IL-12 p40 and p35 mRNA expression. Both p40 and p35 mRNA levels were approximately equal. IFN-γ also greatly promoted the LPS-induced secretion of IL-12 p70 in MPSMs. The Proteasome Inhibitor I (PSI) could block the expression of IL-12 p40 and p35 mRNA, and the degradation of κBα induced by LPS or LPS/IFN-γ. EMSA showed that LPS could augment the NF-κB binding activity to p40 promoter DNA. However, IFN-γ could neither enhance the LPS-induced NF-κB activity nor promote the degradation of kBa. Taken together, the data suggest: (i) IFN-γ/LPS could strongly induce the expression of IL-12 p40 and p35 mRNA; both the expression levels were equal; this phenomenon coincided with the high-level secretion of IL-12 p70 induced by IFN-γ/LPS; (ii) NF-KB signal pathway is essential for IFN-γ/LPS to induce IL-12 mRNA expression; (iii) by blocking the degradation of κB, the PSI suppresses the IL-12 p40/p35 mRNA expression induced by LPS and IFN-γ/LPS; (iv) NF-KB signal may not be involved in the mechanism by which IFN-γ enhanced the expression of the LPS-induced IL-12 p40/p35 mRNA.
文摘目的:探讨白细胞介素(interleukin,IL)-12p40、干扰素(interferon,IFN)-γ在缓解复发型多发性硬化(relap-sing remitting form of multiple sclerosis,RRMS)发病中的病生机制。方法:选取RRMS急性期患者24例及作为对照组的非炎性神经系统疾病(non-inflammatory neurological diseases,NIND)患者12例,应用ELISA法测定受试者血清及脑脊液中IL-12p40、IFN-γ水平。结果:RRMS组血清中IL-12p40水平明显下降,IFN-γ水平与NIND组相比无统计学意义。脑脊液中IL-12p40、IFN-γ水平在两组中可检测到的阳性例数均低,相比之下无统计学意义。结论:IL-12p40参与了多发性硬化发病的免疫病理过程。
文摘therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL12p40)has been established both in vitro and in vivo,warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3%body surface area involvement were enrolled infour dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75%improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.
