Essential involvement of cross‐talk between IFN‐γ and TNF‐α in CXCL10 production in human THP‐1 monocytes

Interferon (IFN)-γ-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-γ depending on cell type, the mechanisms regulating CXCL10 production following treatment with combination of IFN-γ and TNF-α have not been adequately elucidated in human monocytes. In this study, we showed that TNF-α had more potential than IFN-γ to induce CXCL10 production in THP-1 monocytes. Furthermore, IFN-γ synergistically enhanced the production of CXCL10 in parallel with the activation of NF-κB in TNF-α-stimulated THP-1 cells. Blockage of STAT1 or NF-κB suppressed CXCL10 production. JAKs inhibitors suppressed IFN-γ plus TNF-α-induced production of CXCL10 in parallel with activation of STAT1 and NF-κB, while ERK inhibitor suppressed production of CXCL10 as well as activation of NF-κB, but not that of STAT1. IFN-γ-induced phosphorylation of JAK1 and JAK2, whereas TNF-α induced phosphorylation of ERK1/2. Interestingly, IFN-γ alone had no effect on phosphorylation and degradation of IκB-α, whereas it significantly promoted TNF-α-induced phosphorylation and degradation of IκB-α. These results suggest that TNF-α induces CXCL10 production by activating NF-κB through ERK and that IFN-γ induces CXCL10 production by increasing the activation of STAT1 through JAKs pathways. Of note, TNF-α-induced NF-κB may be the primary pathway contributing to CXCL10 production in THP-1 cells. IFN-γ potentiates TNF-α-induced CXCL10 production in THP-1 cells by increasing the activation of STAT1 and NF-κB through JAK1 and JAK2. J. Cell. Physiol. 220: 690–697, 2009. © 2009 Wiley-Liss, Inc.