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Infection and Immunity, May 2005, p. 2728-2735, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2728-2735.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Outer Membrane Protein P6 of Nontypeable Haemophilus influenzae Is a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines

Charles S. Berenson,* Timothy F. Murphy, Catherine T. Wrona, and Sanjay Sethi

Infectious Disease Division, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York 14215

Received 16 September 2004/ Returned for modification 4 November 2004/ Accepted 22 January 2005

Interactions of nontypeable Haemophilus influenzae (NTHI) with human macrophages contribute to the pathogenesis of NTHI-induced infection in humans. However, the immunologic mechanisms that initiate and perpetuate NTHI-mediated macrophage responses have not been well explored. Outer membrane protein (OMP) P6 is a conserved lipoprotein expressed by NTHI in vivo that possesses a Pam3Cys terminal motif, characteristic of immunoactive bacterial lipoproteins associated with Toll-like receptor signaling. We theorized that OMP P6 is a potent immunomodulator of human macrophages. To test this hypothesis, we purified OMP P6 as well as OMP P2, the predominant NTHI outer membrane protein, and lipooligosaccharide (LOS), the specific endotoxin of NTHI, from NTHI strain 1479. Human blood monocyte-derived macrophages, purified from healthy donors, were incubated with each outer membrane constituent, and cytokine production of macrophage supernatants interleukin-1ß (IL-1ß), tumor necrosis factor {alpha} (TNF-{alpha}), IL-10, IL-12, and IL-8 was measured. OMP P6 selectively upregulated IL-10, TNF-{alpha}, and IL-8. While OMP P6 (0.1 µg/ml for 8 h) elicited slightly greater concentrations of IL-10, it resulted in over ninefold greater concentrations of TNF-{alpha} and over fourfold greater concentrations of IL-8 than did OMP P2. OMP P6 at doses as low as 10 pg/ml was still effective at induction of macrophage IL-8, while OMP P2 and LOS were not. OMP P6 of NTHI is a specific trigger of bacteria-induced human macrophage inflammatory events, with IL-8 and TNF-{alpha} as key effectors of P6-induced macrophage responses.

* Corresponding author. Mailing address: Division of Infectious Diseases (151), VA Western NY Healthcare System, 3495 Bailey Avenue, Buffalo, New York 14215. Phone: (716) 862-6529. Fax: (716) 862-6526. E-mail: berenson{at}acsu.buffalo.edu.

Editor: J. B. Bliska

Infection and Immunity, May 2005, p. 2728-2735, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2728-2735.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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