1. Essential involvement of cross-talk between IFN-gamma and TNF-alpha in CXCL10 production in human THP-1 monocytes.
- Author
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Qi XF, Kim DH, Yoon YS, Jin D, Huang XZ, Li JH, Deung YK, and Lee KJ
- Subjects
- Cell Line, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, I-kappa B Proteins metabolism, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Mitogen-Activated Protein Kinase Kinases metabolism, Monocytes drug effects, Monocytes enzymology, NF-KappaB Inhibitor alpha, NF-kappa B metabolism, Phosphorylation, Protein Kinase Inhibitors pharmacology, Receptors, Tumor Necrosis Factor, Type I metabolism, Receptors, Tumor Necrosis Factor, Type II metabolism, Recombinant Proteins metabolism, STAT1 Transcription Factor metabolism, Up-Regulation, Chemokine CXCL10 metabolism, Interferon-gamma metabolism, Monocytes immunology, Signal Transduction drug effects, Tumor Necrosis Factor-alpha metabolism
- Abstract
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.
- Published
- 2009
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