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Infection and Immunity, September 2004, p. 5308-5314, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5308-5314.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Live Lactobacillus reuteri Is Essential for the Inhibitory Effect on Tumor Necrosis Factor Alpha-Induced Interleukin-8 Expression

Donglai Ma, Paul Forsythe, and John Bienenstock*

Department of Pathology and Molecular Medicine, McMaster University,1 The Brain-Body Institute, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada2

Received 5 December 2003/ Returned for modification 26 February 2004/ Accepted 21 May 2004

The mechanism of the apparent anti-inflammatory action of probiotic organisms is unclear. Lactobacillus reuteri is effective in inhibiting colitis in interleukin-10 (IL-10)-deficient mice. Nerve growth factor (NGF), in addition to its activity on neuronal cell growth, has significant anti-inflammatory effects in several experimental systems in vitro and in vivo, including a model of colitis. Our experiments were designed to explore the mechanism of effect of L. reuteri in the human epithelial cell lines T84 and HT29 on cytokine and NGF synthesis and IL-8 response to tumor necrosis factor alpha (TNF-{alpha}). Epithelial cells were cultured for various times with live and killed L. reuteri and examined by reverse transcription-PCR for NGF, IL-10, and TNF-{alpha}-induced IL-8 expression. An enzyme-linked immunosorbent assay was used to quantitate intracellular IL-8 and secreted product. Western blotting and confocal microscopy were used to determine the effects on I{kappa}B and NF-{kappa}B, respectively. Live but not heat-killed or gamma-irradiated L. reuteri upregulated NGF and dose dependently inhibited constitutive synthesis by T84 and HT29 cells of IL-8 and that induced by TNF-{alpha} in terms of mRNA and intracellular and secreted protein. Similarly, L. reuteri inhibited IL-8 synthesis induced by Salmonella enterica serovar Typhimurium. L. reuteri required preincubation and adherence for effect, inhibited translocation of NF-{kappa}B to the nuclei of HeLa cells, and prevented degradation of I{kappa}B. Neither cellular lysates nor media supernatants had any effect on TNF-{alpha}-induced IL-8. The conclusion is that L. reuteri has potent direct anti-inflammatory activity on human epithelial cells, which is likely to be related to the activity of ingested probiotics. L. reuteri also upregulates an unusual anti-inflammatory molecule, NGF, and inhibits NF-{kappa}B translocation to the nucleus.

* Corresponding author. Mailing address: Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St. West, Room 3N26H, Hamilton, Ontario L8N 3Z5, Canada. Phone: (905) 525-9140, ext. 22328. Fax: (905) 522-4936. E-mail: bienens{at}mcmaster.ca.

Editor: F. C. Fang

Infection and Immunity, September 2004, p. 5308-5314, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5308-5314.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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