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* Department of Pathology, University of Verona, Verona, Italy;
Pulmonary Division, University of Sherbrooke, Sherbrooke, Quebec, Canada;
Fondazione Humanitas per la Ricerca, Rozzano, Italy; and
Institute of General Pathology, University of Milano, Milano, Italy
LPS activates both MyD88-dependent and -independent signaling via TLR4, but the extent to which each cascade is operative in different cell types remains unclear. This prompted us to revisit the intriguing issue of CXCL10 production, which we previously showed to be inducible in neutrophils stimulated with LPS and IFN-
but not with either stimulus alone, contrary to other myeloid cells. We now report that in neutrophils the MyD88-independent pathway is not activated by LPS. Indeed, microarray and real-time PCR experiments showed that neither IFN
nor IFN-dependent genes (including CXCL10) are inducible in LPS-treated neutrophils, in contrast to monocytes. Further investigation into the inability of LPS to promote IFN expression in neutrophils revealed that the transcription factors regulating the IFN enhanceosome, such as IFN-regulatory factor-3 and AP-1, are not activated in LPS-treated neutrophils as revealed by lack of dimerization, nuclear translocation, confocal microscopy, and inducible binding to DNA. Moreover, we show that the upstream TANK-binding kinase-1 is not activated by LPS in neutrophils. A lack of IFN/CXCL10 mRNA expression and IFN-regulatory factor 3 activation was also observed in myeloid leukemia HL60 cells differentiated to granulocytes and then stimulated with LPS, indicating that the inability of neutrophils to activate the MyD88-independent pathway represents a feature of their terminal maturation. These results identify a disconnected activation of the two signaling pathways downstream of TLR4 in key cellular components of the inflammatory and immune responses and help us to better understand the primordial role of neutrophils in host defense against nonviral infections.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Ministero dell’Istruzione, dell’Università e della Ricerca (Progetti di Rilevante Interesse Nazionale 2005, Fondo di Investimento per la Ricerca di Base, and 60%), Fondazione Cassa di Risparmio di Verona-Vicenza-Ancona e Belluno, Associazione Italiana per la Ricerca sul Cancro, and the Canadian Institutes for Health Research. A.C. is the recipient of a Canadian Institutes for Health Research Studentship. P.P.McD. is a scholar of the Fonds de la Recherche en Santé du Québec.
2 N.T. and V.L.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Marco A. Cassatella, Department Pathology, Division of General Pathology, Strada Le Grazie 4, Verona, Italy. E-mail address: marco.cassatella{at}univr.it
4 Abbreviations used in this paper: IRF, IFN-regulatory factor; CHX, cycloheximide; DC, dendritic cell; DEX, dexamethasone; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; IKK, I
B kinase; MNE, mean normalized expression; mono-DC, monocyte-derived DC; MX1, myxovirus resistance 1; NAP1, NF-B-activating kinase-associated protein 1; RIPA, radioimmune precipitation assay; SARM, sterile 
and HEAT-armadillo motif; SHP, Src homology 2 domain-containing tyrosine phosphatase; TIR, Toll/IL-1R; TICAM, TIR-containing adapter molecule; TIRAP/MAL, TIR domain-containing adapter protein/MyD88 adapter-like protein; TRIF, TIR domain-containing adapter inducing IFN; TRAF, TNF receptor-associated factor; TRAM, TRIF-related adapter molecule; TBK, TRAF family-associated NF-B binding kinase (TANK) binding kinase.
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