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

J Cell Physiol. 2009 Sep;220(3):690-7. doi: 10.1002/jcp.21815.


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.

MeSH terms

  • Cell Line
  • Chemokine CXCL10 / metabolism*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • Interferon-gamma / 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
  • Monocytes / immunology*
  • 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
  • Signal Transduction* / drug effects
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation


  • CXCL10 protein, human
  • Chemokine CXCL10
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Protein Kinase Inhibitors
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Interferon-gamma
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases