Post-translational inhibition of IP-10 secretion in IEC by probiotic bacteria: impact on chronic inflammation

Gabriele Hoermannsperger, Thomas Clavel, Micha Hoffmann, Caroline Reiff, Denise Kelly, Gunnar Loh, Michael Blaut, Gabriele Hölzlwimmer, Melanie Laschinger, Dirk Haller

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Abstract

BACKGROUND: Clinical and experimental studies suggest that the probiotic mixture VSL#3 has protective activities in the context of inflammatory bowel disease (IBD). The aim of the study was to reveal bacterial strain-specific molecular mechanisms underlying the anti-inflammatory potential of VSL#3 in intestinal epithelial cells (IEC). METHODOLOGY/PRINCIPAL FINDINGS: VSL#3 inhibited TNF-induced secretion of the T-cell chemokine interferon-inducible protein (IP-10) in Mode-K cells. Lactobacillus casei (L. casei) cell surface proteins were identified as active anti-inflammatory components of VSL#3. Interestingly, L. casei failed to block TNF-induced IP-10 promoter activity or IP-10 gene transcription at the mRNA expression level but completely inhibited IP-10 protein secretion as well as IP-10-mediated T-cell transmigration. Kinetic studies, pulse-chase experiments and the use of a pharmacological inhibitor for the export machinery (brefeldin A) showed that L. casei did not impair initial IP-10 production but decreased intracellular IP-10 protein stability as a result of blocked IP-10 secretion. Although L. casei induced IP-10 ubiquitination, the inhibition of proteasomal or lysosomal degradation did not prevent the loss of intracellular IP-10. Most important for the mechanistic understanding, the inhibition of vesicular trafficking by 3-methyladenine (3-MA) inhibited IP-10 but not IL-6 expression, mimicking the inhibitory effects of L. casei. These findings suggest that L. casei impairs vesicular pathways important for the secretion of IP-10, followed by subsequent degradation of the proinflammatory chemokine. Feeding studies in TNF(DeltaARE) and IL-10(-/-) mice revealed a compartimentalized protection of VSL#3 on the development of cecal but not on ileal or colonic inflammation. Consistent with reduced tissue pathology in IL-10(-/-) mice, IP-10 protein expression was reduced in primary epithelial cells. CONCLUSIONS/SIGNIFICANCE: We demonstrate segment specific effects of probiotic intervention that correlate with reduced IP-10 protein expression in the native epithelium. Furthermore, we revealed post-translational degradation of IP-10 protein in IEC to be the molecular mechanism underlying the anti-inflammatory effect.
Original languageEnglish
Article numbere4365
Number of pages17
JournalPloS ONE
Volume4
Issue number2
DOIs
Publication statusPublished - 2009

Keywords

  • animals
  • autophagy
  • bacterial Proteins
  • chemokine CXCL10
  • chemotaxis
  • chronic disease
  • colitis
  • epithelial cells
  • humans
  • inflammation
  • intestines
  • intracellular space
  • Lactobacillus casei
  • lysosomes
  • mice
  • organ specificity
  • probiotics
  • protein processing, post-translational
  • signal transduction
  • transcription, genetic
  • tumor necrosis factor-alpha

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    Hoermannsperger, G., Clavel, T., Hoffmann, M., Reiff, C., Kelly, D., Loh, G., Blaut, M., Hölzlwimmer, G., Laschinger, M., & Haller, D. (2009). Post-translational inhibition of IP-10 secretion in IEC by probiotic bacteria: impact on chronic inflammation. PloS ONE, 4(2), [e4365]. https://doi.org/10.1371/journal.pone.0004365