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

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 DARE and IL-10 2/2 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 2/2 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.

Chemokines and Their Receptors Are Key Players in the Orchestra That Regulates Wound Healing

“…For example, surface proteins of Lactobacillus casei were found to be anti-inflammatory by decreasing the intracellular CXCL10 protein stability, resulting in inhibition of protein secretion and function. 65 …”

The Role of Probiotics in Lipopolysaccharide-Induced Autophagy in Intestinal Epithelial Cells

“…Oral administration of specific probiotics can reduce experimental colitis in IL-10-deficient mice [19], and in clinical studies probiotics affected gut flora so as to prevent or treat different gut disorders ranging from diarrhea and pouchitis to chronic relapsing IBD [20,21]. However, the molecular mechanisms by which probiotics exert positive effects on gut homeostasis remains unknown.…”

A Strain of Lactobacillus casei Inhibits the Effector Phase of Immune Inflammation

“…Similar effects were observed when lactobacilli were administered intranasally (25)(26)(27), s.c. (28), or i.p (29). Cell wall molecules from Lactobacillus casei inhibited the secretion of IP-10 by an intestinal epithelial cell line induced by TNF-a (30). The protective effects of probiotics were proposed to result from an altered Ag presentation by dendritic cells, leading to decreased IgE responses (31), a skewed Th1/Th2 polarization (24), or the induction of regulatory T cells (21,32).…”