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J. Biol. Chem., Vol. 281, Issue 41, 31119-31130, October 13, 2006

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Contribution of Interferon- to the Murine Macrophage Response to the Toll-like Receptor 4 Agonist, Lipopolysaccharide^*

Karen E. Thomas, Carole L. Galligan, Raj Deonarain Newman, Eleanor N. Fish, and Stefanie N. Vogel¹

From the Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland 21201 and the Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada

Interferon- (IFN-) has been identified as the signature cytokine induced via the Toll-like receptor (TLR) 4, "MyD88-independent" signaling pathway in macrophages stimulated by Gram-negative bacterial lipopolysaccharide (LPS). In this study, we analyzed the responses of macrophages derived from wild-type (IFN-^+/+) mice or mice with a targeted mutation in IFN- (IFN-^-/-) to the prototype TLR4 agonist, Escherichia coli LPS. A comparison of basal and LPS-induced gene expression (by reverse transcription-PCR, real-time PCR, and Affymetrix microarray analyses) resulted in the identification of four distinct patterns of gene expression affected by IFN- deficiency. Analysis of a subset of each group of differentially regulated genes by computer-assisted promoter analysis revealed putative IFN-responsive elements in all genes examined. LPS-induced activation of intracellular signaling molecules, STAT1 Tyr-701, STAT1 Ser-727, and Akt, but not p38, JNK, and ERK MAPK proteins, was significantly diminished in IFN-^-/- versus IFN-^+/+ macrophages. "Priming" of IFN-^-/- macrophages with exogenous recombinant IFN- significantly increased levels of LPS-induced gene expression for induction of monocyte chemotactic protein 5, inducible nitric-oxide synthase, IP-10, and IL-12 p40 mRNA, whereas no increase or relatively small increases were observed for IL-1, IL-6, monocyte chemotactic protein 1, and MyD88 mRNA. Finally, IFN-^-/- mice challenged in vivo with LPS exhibited increased survival when compared with wild-type IFN-^+/+ controls, indicating that IFN- contributes to LPS-induced lethality; however, not to the extent that one observes in mice with more complete pathway deficiencies (e.g. TLR4^-/- or TRIF^-/- mice). Collectively, these findings reveal unanticipated regulatory roles for IFN- in response to LPS in vitro and in vivo.

Received for publication, May 23, 2006 , and in revised form, July 12, 2006.

^* This work was supported by National Institutes of Health Grant AI18797 (to S. N. V.) and by the Canadian Institutes of Health Research (Grant MOP 15094 to E. N. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Maryland, Baltimore, 660 W. Redwood St., Rm. 324, Baltimore, MD 21201. Tel.: 410-706-4838; Fax: 410-706-8607; E-mail: svogel{at}som.umaryland.edu.

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