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Synergistic Induction of Inflammation by Bacterial Products Lipopolysaccharide and fMLP: An Important Microbial Pathogenic Mechanism¹

Ling-Yu Chen^*, Warren W. Pan^*, Miao Chen^*, Jain-Dong Li, Wei Liu^*,, Guoqiang Chen, Shuang Huang, Thomas J. Papadimos^* and Zhixing K. Pan^2,*,

^* Department of Medical Microbiology and Immunology, Medical University of Ohio, Toledo, OH 43614; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; Department of Pathophysiology, Shanghai Jiao-Tong University School of Medicine, Luwan, Shanghai, China; and Department of Immunology and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037

A wide variety of stimuli have been shown to induce inflammation, but bacteria products/components are considered the major inducers during bacterial infections. We previously demonstrated that bacterial products/components such as LPS, a glycolipid component of the bacterial outer membrane, and formylated peptides (fMLP), a bacterial-derived peptide, induced proinflammatory cytokine gene expression in human peripheral blood monocytes. We now present evidence that mixtures of bacterial products/components LPS and fMLP behave synergistically in the induction of inflammation in vitro and in vivo. Furthermore, our results indicate that the TLR4 and the IKKβ-IB signaling pathways are involved in the synergistic induction of inflammatory cytokines. The mechanism of synergistic activation of NF-B is depended on nuclear translocation of p65 and phosphorylation of p65 at both Ser536 and Ser276 sites. These results demonstrate an important role for bacterial products/components from lysed bacteria in the pathogenesis of infectious diseases. We believe that this synergistic induction of inflammation by bacterial products LPS and fMLP represents an important pathogenic mechanism during bacterial infection, which may suggest novel therapeutic strategies or targets to minimize host injury following bacterial infection.

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 U.S. Public Health Service Grants AI43524 and HL69425 (to Z.K.P.) and National Institutes of Health Training Grant T32 AI 07469 to L.-Y.C. This work was also supported in part by the Sam and Ross Stein Charitable Trust and National Institutes of Health Grant M01RR00833 provided to the General Clinical Research Center of the Scripps Research Institute.

² Address correspondence and reprint requests to Dr. Zhixing K. Pan, Department of Medical Microbiology and Immunology, Medical University of Ohio, 3035 Arlington Avenue, Toledo, OH 43614. E-mail address: kevin.pan{at}utoledo.edu

³ Abbreviations used in this paper: EMSA, electrophoretic mobility shift assay; BAL, bronchoalveolar lavage; BALF, BAL fluid; FPR, N-formyl peptide receptor; siRNA, small interfering RNA; WT, wild type.