This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, B. Articles by Li, J.-D. Search for Related Content PubMed PubMed Citation Articles by Wang, B. Articles by Li, J.-D.

 Previous Article  |  Next Article 

Infection and Immunity, October 2003, p. 5523-5530, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5523-5530.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Up-Regulation of Interleukin-8 by Novel Small Cytoplasmic Molecules of Nontypeable Haemophilus influenzae via p38 and Extracellular Signal-Regulated Kinase Pathways

Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057,¹ Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455²

Received 18 April 2003/ Returned for modification 29 May 2003/ Accepted 30 June 2003

Nontypeable Haemophilus influenzae (NTHI) is an important etiological agent of otitis media (OM) and of exacerbated chronic obstructive pulmonary diseases (COPD). Inflammation is a hallmark of both diseases. Interleukin-8 (IL-8), one of the important inflammatory mediators, is induced by NTHI and may play a significant role in the pathogenesis of these diseases. Our studies demonstrated that a soluble cytoplasmic fraction (SCF) from NTHI induced much greater IL-8 expression by human epithelial cells than did NTHI lipooligosaccharides and envelope proteins. The IL-8-inducing activity was associated with molecules of 3 kDa from SCF and was peptidase and lipase sensitive, suggesting that small lipopeptides are responsible for the strong IL-8 induction. Moreover, multiple intracellular signaling pathways were activated in response to cytoplasmic molecules. The results indicated that the p38 mitogen-activated protein kinase (MAPK) and Src-dependent Raf-1-Mek1/2-extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathways are required for NTHI-induced IL-8 production. In contrast, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway did not affect IL-8 expression, although this pathway was concomitantly activated upon exposure to NTHI SCF. The PI3K-Akt pathway was also directly activated by IL-8 and significantly inhibited by an antagonist of IL-8 receptors during NTHI stimulation. These results indicated that the PI3K-Akt pathway is activated in response to IL-8 that is induced by NTHI and may lead to other important epithelial cell responses. This work provides insight into essential molecular and cellular events that may impact on the pathogenesis of OM and COPD and identifies rational targets for anti-inflammatory intervention.

Editor: J. D. Clements

This article has been cited by other articles:

• Tudhope, S. J., Finney-Hayward, T. K., Nicholson, A. G., Mayer, R. J., Barnette, M. S., Barnes, P. J., Donnelly, L. E. (2008). Different Mitogen-Activated Protein Kinase-Dependent Cytokine Responses in Cells of the Monocyte Lineage. J. Pharmacol. Exp. Ther. 324: 306-312 [Abstract] [Full Text]  
• Venza, I., Cucinotta, M., Caristi, S., Mancuso, G., Teti, D. (2007). Transcriptional Regulation of IL-8 by Staphylococcus aureus in Human Conjunctival Cells Involves Activation of AP-1. IOVS 48: 270-276 [Abstract] [Full Text]  
• Trevino, J. G., Summy, J. M., Gray, M. J., Nilsson, M. B., Lesslie, D. P., Baker, C. H., Gallick, G. E. (2005). Expression and Activity of Src Regulate Interleukin-8 Expression in Pancreatic Adenocarcinoma Cells: Implications for Angiogenesis. Cancer Res. 65: 7214-7222 [Abstract] [Full Text]  
• Chin, C. L., Manzel, L. J., Lehman, E. E., Humlicek, A. L., Shi, L., Starner, T. D., Denning, G. M., Murphy, T. F., Sethi, S., Look, D. C. (2005). Haemophilus influenzae from Patients with Chronic Obstructive Pulmonary Disease Exacerbation Induce More Inflammation than Colonizers. Am. J. Respir. Crit. Care Med. 172: 85-91 [Abstract] [Full Text]  
• Berenson, C. S., Murphy, T. F., Wrona, C. T., Sethi, S. (2005). Outer Membrane Protein P6 of Nontypeable Haemophilus influenzae Is a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines. Infect. Immun. 73: 2728-2735 [Abstract] [Full Text]  
• Ratner, A. J., Lysenko, E. S., Paul, M. N., Weiser, J. N. (2005). Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces. Proc. Natl. Acad. Sci. USA 102: 3429-3434 [Abstract] [Full Text]  
• Barnes, P. J. (2004). Mediators of Chronic Obstructive Pulmonary Disease. Pharmacol. Rev. 56: 515-548 [Abstract] [Full Text]  
• Palacios, S. D., Pak, K., Rivkin, A. Z., Kayali, A. G., Austen, D., Aletsee, C., Melhus, A., Webster, N. J. G., Ryan, A. F. (2004). Role of p38 Mitogen-Activated Protein Kinase in Middle Ear Mucosa Hyperplasia during Bacterial Otitis Media. Infect. Immun. 72: 4662-4667 [Abstract] [Full Text]