Essential involvement of cross-talk between IFN-gamma and TNF-alpha in CXCL10 production in human THP-1 monocytes.

Qi XF; Kim DH; Yoon YS

摘要

Interferon (IFN)-gamma-induced protein 10 (IP-10/CXCL10), a CXC chemokine, has been documented in several inflammatory and autoimmune disorders including atopic dermatitis and bronchial asthma. Although CXCL10 could be induced by IFN-gamma depending on cell type, the mechanisms regulating CXCL10 production following treatment with combination of IFN-gamma and TNF-alpha have not been adequately elucidated in human monocytes. In this study, we showed that TNF-alpha had more potential than IFN-gamma to induce CXCL10 production in THP-1 monocytes. Furthermore, IFN-gamma synergistically enhanced the production of CXCL10 in parallel with the activation of NF-kappaB in TNF-alpha-stimulated THP-1 cells. Blockage of STAT1 or NF-kappaB suppressed CXCL10 production. JAKs inhibitors suppressed IFN-gamma plus TNF-alpha-induced production of CXCL10 in parallel with activation of STAT1 and NF-kappaB, while ERK inhibitor suppressed production of CXCL10 as well as activation of NF-kappaB, but not that of STAT1. IFN-gamma-induced phosphorylation of JAK1 and JAK2, whereas TNF-alpha induced phosphorylation of ERK1/2. Interestingly, IFN-gamma alone had no effect on phosphorylation and degradation of IkappaB-alpha, whereas it significantly promoted TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha. These results suggest that TNF-alpha induces CXCL10 production by activating NF-kappaB through ERK and that IFN-gamma induces CXCL10 production by increasing the activation of STAT1 through JAKs pathways. Of note, TNF-alpha-induced NF-kappaB may be the primary pathway contributing to CXCL10 production in THP-1 cells. IFN-gamma potentiates TNF-alpha-induced CXCL10 production in THP-1 cells by increasing the activation of STAT1 and NF-kappaB through JAK1 and JAK2.

机译：干扰素(IFN)射线诱发蛋白10科学家趋化因子(IP-10 / CXCL10),记录在一些炎症和自身免疫障碍包括过敏性皮炎和支气管哮喘。IFN-gamma根据细胞类型不同,引起的CXCL10生产后的调节机制IFN-gamma和治疗tnf尚未充分阐明人类单核细胞。比IFN-gamma tnf有更多的潜力在THP-1单核细胞诱导CXCL10生产。此外,IFN-gamma表现为协同作用增强生产CXCL10并行的激活NF-kappaB TNF-alpha-stimulatedTHP-1细胞。抑制CXCL10生产。抑制IFN-gamma + TNF-alpha-induced生产CXCL10与激活STAT1和NF-kappaB,而ERK抑制剂抑制CXCL10以及生产STAT1的激活NF-kappaB,但不是。IFN-gamma-induced JAK1和磷酸化JAK2,而tnf诱导磷酸化ERK1/2。影响磷酸化和退化IkappaB-alpha,而它显著提升TNF-alpha-induced磷酸化和退化IkappaB-alpha。通过激活tnf诱导CXCL10生产通过ERK和NF-kappaB IFN-gamma诱发CXCL10生产增加的激活通过木菠萝STAT1通路。TNF-alpha-induced NF-kappaB可能是主要的途径导致CXCL10生产THP-1细胞。在THP-1 TNF-alpha-induced CXCL10生产通过增加STAT1的活化和细胞NF-kappaB无论是JAK1和JAK2。

Essential involvement of cross-talk between IFN-gamma and TNF-alpha in CXCL10 production in human THP-1 monocytes.

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