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Modulation of cellular innate immune responses by lactobacilli

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Modulation of cellular innate immune responses

by lactobacilli

av

Mattias Karlsson

Akademisk avhandling

Avhandling för filosofie doktorsexamen i biologi, som enligt beslut av rektor kommer att försvaras offentligt

Fredagen den 1 juni 2012 kl. 13.00, Hörsal BIO, Forumhuset, Örebro universitet

Opponent: Professor Gilbert Donders Avdelningen för obstetrik och gynekologi,

Gasthuisbergs universitetssjukhus Leuven, Belgien

Örebro universitet

Institutionen för naturvetenskap och teknik 701 82 Örebro

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Abstract

Mattias Karlsson (2012): Modulation of cellular innate immune responses by lactobacilli. Örebro Studies in Life Science 10, 84 pp.

Lactobacillus is a genus of lactic acid bacteria frequently used as health-promoting probiotics. Using probiotics to treat or prevent infections is a novel experimental approach with vast impact on future therapy. Lactoba-cillus rhamnosus GR-1 is a probiotic investigated for its ability to reduce urogenital disease including urinary tract infections caused by pathogenic Escherichia coli. L. rhamnosus GR-1 has been shown to modulate immu-nity, thought to influence its probiotic effect. In this thesis, the aim was to study immunomodulation by L. rhamnosus GR-1 and other lactobacilli, with emphasis on elicited immune responses such as nuclear factor-kappaB (NF-κB) activation and cytokine release from human urothelial cells.

Viable, heat-killed, and isolated released products from L. rhamnosus GR-1 augmented NF-κB activation in E. coli-challenged urothelial cells. Blocking of lipopolysaccharide binding to toll-like receptor 4 completely quelled this augmentation. Size-fractionation, urothelial cell challenge, and two-dimensional gel electrophoresis of L. rhamnosus GR-1 released prod-ucts presented several candidate proteins with NF-κB modulatory actions including chaperonin GroEL, elongation factur Tu, and a protein from the NLP/P60 protein family. While tumor necrosis factor was correspondingly augmented by L. rhamnosus GR-1, the release of two other cytokines, interleukin (IL)-6 and CXCL8, was reduced. Similar effects were observed in macrophage-like cells stimulated with L. rhamnosus GR-1.

Many immunomodulatory effects of lactobacilli are believed to be spe-cies and strain dependent. Therefore, twelve Lactobacillus strains were used to screen for their effects on CXCL8 release from urothelial cells. A majority of these strains were able to influence CXCL8 release from the cells. Phylogenetic analysis revealed close evolutionary linkage between lactobacilli with similar actions on CXCL8. Increased knowledge on pro-biotic bacterial products and the mechanism(s) of action could lead to im-proved future treatments for infections.

Keywords: cytokines, immunomodulation, lactobacilli, probiotics, urinary tract infections, urothelium.

Mattias Karlsson, School of Science and Technology

References

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