Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN-gamma 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 IFN-gamma, as well as by neutrophils, though the latter require a costimulation with IFN-gamma and LPS. In this study, we investigated the molecular mechanism(s) whereby IFN-gamma and TLR4 ligation synergize to induce CXCL10 expression in neutrophils. By primary transcript real-time PCR analysis, we demonstrate that the CXCL10 gene is transcriptionally induced by the LPS plus IFN-gamma combination in neutrophils, consistent with previous studies showing that increased CXCL10 gene expression does not reflect enhanced mRNA stability. The IFN-gamma-induced STAT1 activation and the lipopolysaccharide (LPS)-induced NF-kappaB activation were not enhanced if neutrophils were exposed to both stimuli, whereas both transcription factors were activated by IFN-gamma or LPS in monocytes. Finally, pharmacological inhibitors of NF-kappaB demonstrated its role in the induction of CXCL10 expression by LPS plus IFN-gamma in neutrophils, and by LPS or IFN-gamma in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN-gamma toward CXCL10 gene expression likely reflects the cooperative induction of the NF-kappaB and STAT1 transcription factors by LPS and IFN-gamma, respectively.
Department of Pathology, University of Verona, Verona, Italy.
Nicola
N
Tamassia
Federica
F
Calzetti
Thornin
T
Ear
Alexandre
A
Cloutier
Sara
S
Gasperini
Flavia
F
Bazzoni
Patrick P
PP
McDonald
Marco A
MA
Cassatella
D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019000:Phosphotyrosine; D007371:Interferon-gamma