DMPD: Dynamic Macrophage Pathway Database

Ayumu Saito 1 Masao Nagasaki 1 Andre Fujita 2

s-ayumu@ims.u-tokyo.ac.jp masao@ims.u-tokyo.ac.jp andrefujita@riken.jp

Kazuko Ueno 1 Emi Ikeda 1 Satoru Miyano 1

uepi@ims.ims.u-tokyo.ac.jp e-ikeda@ims.u-tokyo.ac.jp miyano@ims.u-tokyo.ac.jp

1 Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shi-rokanedai, Minato-ku, Tokyo 108-8639, Japan

2 Computational Science Research Program, RIKEN, 2-1 Hirosawa, Wako, Saitama,351-0198, Japan

Keywords: macrophage, immune system, LPS, database

1 Introduction

The immune system has evolved as a defense mechanism against pathogenic microbes [3].

The immune system is closely connected with the hematologic system since white blood cells arekey players in the lymphoid system. Cellular participants in the immune and inflammatory responsesinclude antigen presenting cells and phagocytic cells, such as macrophages.

Significant progress has been made recently in understanding the biochemical mechanisms by whichlipopolysaccharide (LPS), a bacterial endotoxin, activates immune cells, particularly macrophages [4].

Macrophage over-reaction to the presence of LPS can lead to sepsis, septic shock, or systemicinflammatory response syndrome due to production of a variety of inflammatory cytokines by activatedmacrophages. It is well-known that macrophages stimulated with LPS release tumor necrosis (TNF)and interleukins (IL-1, IL-6, IL-8 and IL-12) [1] which are important mediators of sepsis syndromeand the response to Gram-negative bacterial infections. Increasing evidence suggests that monocyticcell from patients with sepsis and septic shock survivors have characteristics of LPS tolerance and aprofoundly altered response to LPS. Despite much effort, unfortunately there is no effective therapyfor this problem. It is estimated that around 50,000 people die each year in the United States of septicshock or systemic inflammatory syndrome [2]. Thus, a more detailed understanding of the molecularmechanisms underlying activation and deactivation of macrophages in response to LPS becomes crucialfor the development of novel therapies for septic shock and the treatment of septic shock survivors [6].

2 Results

In order to help immunologists research for an effective septic shock treatment, the first database thatis specifically focused on LPS-induced macrophage signaling pathways is presented, namely, DynamicMacrophage Pathway CSML Database (DMPD). DMPD contains more than 200 curated pathwaysfor more than 250 genes derived from ≈200 reports (reviews). All data contained in the DMPDcan be exported to a markup language namely Cell System Markup Language (CSML) format [5]and imported by a cell simulator software namely Cell Illustrator (CI) [5] for visualization and alsopathway simulation. Figure 1 illustrates the database scheme. In Figure 2, users can search for aspecific pathway of interest and also obtain information about literature used in annotation. Pathwayfigures are provided in both, png and svg formats. Users can freely access DMPD using an interactiveweb interface at [7].

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Figure 1: Overview of Dynamic Macrophage Path-way Database scheme.

Figure 2: Interactive DMPD web interface.

References

[1] Cohen, J., The immunopathogenesis of sepsis, Nature, 420:885-891, 2002.

[2] Guha, M., Mackman, N., LPS induction of gene expression in human monocytes, Cellular Sig-

nalling, 13:85-94, 2001.

[3] Janeway, C.A., Medzhitov, R., Innate immune recognition, Annu. Rev. Immunol., 20:197-216,2002.

[4] Miller, S.I., Ernst, R.K., Bader, M.W., LPS, TLR4 and infectious disease diversity, Nature Mi-

crobiology, 3:36-46, 2005.

[5] Nagasaki, M., Doi, A., Matsuno, H., Miyano, S., Genomic Object Net: a platform for modelingand simulating biopathways, Applied Bioinformatics, 2:181-184, 2003.

[6] Palsson-McDermott, E.M., O’Neill, L.A.J., Signal transduction by the lipopolysaccharide recep-tor, Toll-like-4, Immunology, 113:153-162, 2004.

[7] http://gnp.hgc.jp

[8] http://gnp.hgc.jp/macrophage/index.html

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