Abstract
VSL#3, a mixture of 8 different probiotic bacteria, has successfully been used in the clinic to treat Ulcerative Colitis. We previously identified the modulation of chemokines as a major mechanism in the protective effect of the VSL#3 in a mouse model of colitis. This was supported by in vitro studies that implicated a role for VSL#3 in the suppression of LPS-induced chemokine production by mouse bone marrow-derived dendritic cells (DC). Herein, we validated these findings employing human monocyte-derived DC. Stimulation of human DC with LPS, VSL#3, or a combination of both resulted in their maturation, evident from enhanced expression of activation markers on the cell-surface, as well as the induction of various chemokines and cytokines. Interestingly, a set of LPS-induced chemokines was identified that were suppressed by VSL#3. These included CXCL9, CXCL10, CCL2, CCL7, and CCL8. In silico approaches identified STAT-1 as a dominant regulator of these chemokines, and this was confirmed by demonstrating that LPS-induced phosphorylation of this transcription factor was inhibited by VSL#3. This indicates that VSL#3 may contribute to the control of inflammation by selective suppression of STAT-1 induced chemokines.
Highlights
The gastrointestinal tract is continuously exposed to foreign antigens – mainly derived from the commensal microflora and/or food antigens [1]
We evaluated the modulation of TLR-4 induced signaling pathways in human dendritic cells (DC) by probiotic bacteria
Stimulation of these immature DC with the TLR4 agonist LPS, the probiotic mixture VSL#3, or a combination of both resulted in a mature phenotype, evident from the enhanced expression of HLADR, CD86, and CD83
Summary
The gastrointestinal tract is continuously exposed to foreign antigens – mainly derived from the commensal microflora and/or food antigens [1]. VSL#3 Dampens Chemokine Expression in DC by Inhibition of STAT-1 inflammatory pathways for appropriate host defense against pathogenic microorganisms while remaining unresponsive to symbiotic bacteria [2, 3]. Under homeostasis conditions little or no inflammation occurs in the gut associated lymphoid tissue (GALT). Genetic defects and impairment of barrier integrity may cause exaggerated immune responses driven by the microflora resulting in the development of intestinal inflammation [4]. Specific lactobacilli and bifidobacteria have been shown efficient in modulating intestinal immunity in homeostasis [5] and conditions of chronic intestinal inflammation like inflammatory bowel disease [6]. Several modes of action of probiotic bacteria have been identified, including restoration of microbial homeostasis through microbe-microbe interactions, pathogen inhibition, enhancement of barrier integrity, or via direct modulation of immune responses [7]
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