Post-Translational Inhibition of IP-10 Secretion in IEC by Probiotic Bacteria: Impact on Chronic Inflammation


Autoria(s): Hoermannsperger, Gabriele; Clavel, Thomas; Hoffmann, Micha; Reiff, Caroline; Kelly, Denise; Loh, Gunnar; Blaut, Michael; Hoelzlwimmer, Gabriele; Laschinger, Melanie; Haller, Dirk
Data(s)

06/02/2009

Resumo

<p>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).</p><p>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 Delta ARE 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.</p><p>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.</p>

Identificador

http://pure.qub.ac.uk/portal/en/publications/posttranslational-inhibition-of-ip10-secretion-in-iec-by-probiotic-bacteria-impact-on-chronic-inflammation(5a4eb91f-0bc8-4342-bb74-db8300d2121a).html

http://dx.doi.org/10.1371/journal.pone.0004365

Idioma(s)

eng

Direitos

info:eu-repo/semantics/restrictedAccess

Fonte

Hoermannsperger , G , Clavel , T , Hoffmann , M , Reiff , C , Kelly , D , Loh , G , Blaut , M , Hoelzlwimmer , G , Laschinger , M & Haller , D 2009 , ' Post-Translational Inhibition of IP-10 Secretion in IEC by Probiotic Bacteria: Impact on Chronic Inflammation ' PLoS One , vol 4 , no. 2 , e4365 , pp. - . DOI: 10.1371/journal.pone.0004365

Tipo

article