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Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components¹

Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Boston, MA 02118

Porphyromonas gingivalis (P. gingivalis) can trigger an inflammatory condition leading to the destruction of periodontal tissues. However P. gingivalis LPS and its fimbriae (FimA) play different roles compared with the live bacteria in the context of intracellular molecule induction and cytokine secretion. To elucidate whether this difference results from different signaling pathways in host immune response to P. gingivalis, its LPS, or its FimA, we examined gene expression profile of human macrophages exposed to P. gingivalis, its LPS, or its FimA. A comparison of gene expression resulted in the identification of three distinct groups of expressed genes. Furthermore, computer-assisted promoter analysis of a subset of each group of differentially regulated genes revealed four putative transcriptional regulation models that associate with transcription factors NFB, IRF7, and KLF4. Using gene knockout mice and siRNA to silence mouse genes, we showed that both TLR2 and TLR7 are essential for the induction of NFB-containing genes and NFB-IFN-sensitive response element (ISRE) cocontaining genes by either P. gingivalis or its purified components. The gene induction via either TLR2 or TLR7 is dependent on both MyD88 and p38 MAPK. However, the unique induction of IFN-β by P. gingivalis LPS requires TLR7 and IFNβR cosignaling, and the induction of ISRE-containing gene is dependent on the activation of IFN-β autocrine loop. Taken together, these data demonstrate that P. gingivalis and its components induce NFB-containing genes through either TLR2- or TLR7-MyD88-p38 MAPK pathway, while P. gingivalis LPS uniquely induces ISRE-containing genes, which requires IFNβR signaling involving IRF7, KLF4, and pY701 STAT1.

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 the National Institute of Dental and Craniofacial Research DE15989 (to S.A.).

² Address correspondence and reprint requests to Dr. Salomon Amar, Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University Medical Center, 700 Albany Street, W-201E, Boston, MA 02118. E-mail address: samar{at}bu.edu

³ Abbreviations used in this paper: FimA, fimbrial protein; ISRE, IFN-sensitive response element; MOI, multiplicity of infection; TF, transcription factor; qRT-PCR, quantitative real-time PCR; RT, reverse transcription; C_T, cycle threshold; KLF, Kruppel-like factor.

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