Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFNγ in human neutrophils

The CXCL10 chemokine is a critical chemoattractant for the recruitment of activated Th1 and NK cells into inflammatory sites. CXCL10 is typically produced by myeloid cells in response to IFNg, as well as by neutrophils, though the latter require a co-stimulation with IFNg and LPS. In this study, we investigated the molecular mechanism(s) whereby IFNg and TLR4 ligation synergize to induce CXCL10 expression in neutrophils. By PT-real time PCR analysis, we demonstrate that the CXCL10 gene is transcriptionally induced by the LPS plus IFNg combination in neutrophils, consistent with previous studies showing that increased CXCL10 gene expression does not reflect enhanced mRNA stability. The IFNg-induced STAT1 activation and the LPS-induced NF-kB activation were not enhanced if neutrophils were exposed to both stimuli, whereas both transcription factors were activated by IFNg or LPS in monocytes. Finally, pharmacological inhibitors of NF-kB demonstrated its role in the induction of CXCL10 expression by LPS plus IFNg in neutrophils, and by LPS or IFNg in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN toward CXCL10 gene expression likely reflects the cooperative induction of the NF-kB and STAT1 transcription factors by LPS and IFNg, respectively.