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Infection and Immunity, August 2000, p. 4430-4440, Vol. 68, No. 8
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Induction of Proinflammatory Cytokines from Human Respiratory Epithelial Cells after Stimulation by Nontypeable Haemophilus influenzae

Daniel L. Clemans,1,* Richard J. Bauer,1,2 Julie A. Hanson,1,2 Monte V. Hobbs,2,dagger Joseph W. St. Geme III,3 Carl F. Marrs,2 and Janet R. Gilsdorf1,2

Department of Pediatrics and Communicable Diseases, University of Michigan Medical School,1 and Department of Epidemiology, University of Michigan School of Public Health,2 Ann Arbor, Michigan 48109, and Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631103

Received 16 February 2000/Returned for modification 6 April 2000/Accepted 28 April 2000

Nontypeable Haemophilus influenzae (NTHi) causes repeated respiratory infections in patients with chronic lung diseases. These infections are characterized by a brisk inflammatory response which results in the accumulation of polymorphonucleated cells in the lungs and is dependent on the expression and secretion of proinflammatory cytokines. We hypothesize that multiple NTHi molecules, including lipooligosaccharide (LOS), mediate cellular interactions with respiratory epithelial cells, leading to the production of proinflammatory cytokines. To address this hypothesis, we exposed 9HTEo- human tracheal epithelial cells to NTHi and compared the resulting profiles of cytokine gene expression and secretion using multiprobe RNase protection assays and enzyme-linked immunosorbent assays (ELISA), respectively. Dose-response experiments demonstrated a maximum stimulation of most cytokines tested, using a ratio of 100 NTHi bacterial cells to 1 9HTEo- tracheal epithelial cell. Compared with purified LOS, NTHi bacterial cells stimulated 3.6- and 4.5-fold increases in epithelial cell expression of interleukin-8 (IL-8) and IL-6 genes, respectively. Similar results were seen with epithelial cell macrophage chemotactic protein 1, IL-1alpha , IL-1beta , and tumor necrosis factor alpha expression. Polymyxin B completely inhibited LOS stimulation but only partially reduced NTHi whole cell stimulation. Taken together, these results suggest that multiple bacterial molecules including LOS contribute to the NTHi stimulation of respiratory epithelial cell cytokine production. Moreover, no correlation was seen between NTHi adherence to epithelial cells mediated by hemagglutinating pili, Hia, HMW1, HMW2, and Hap and epithelial cytokine secretion. These data suggest that bacterial molecules beyond previously described NTHi cell surface adhesins and LOS play a role in the induction of proinflammatory cytokines from respiratory epithelial cells.

* Corresponding author. Mailing address: Department of Pediatrics and Communicable Diseases, The University of Michigan, 109 South Observatory Street, SPH 1/Rm. 2059, Ann Arbor, MI 48109-2029. Phone: (734) 647-3943. Fax: (734) 764-3192. E-mail: dclemans{at}umich.edu.

dagger Deceased.

Infection and Immunity, August 2000, p. 4430-4440, Vol. 68, No. 8
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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